Ten Years of Medicinal Chemistry (2005-2014) in the Journal of Medicinal Chemistry

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Ten Years of Medicinal Chemistry (2005-2014) in the Journal of Medicinal Chemistry:

Country of Contributors, Topics and Public-Private Partnerships.

Luca Costantino*,† and Daniela Barlocco‡

Supplementary Material

Table S1: page 2

Graphs S1A,B: page 25

Table S2: page 26

Graph S2: page 27

Table S3: page 28

Supplementary references: page 30

2005: Articles Title Disease Authors Data Total area Cit. (Rank) (2R)-4-Oxo-4-[3- Diabetes Kim D, Wang L, Beconi M, 48(1), 141-151 486(1) (Trifluoromethyl)-5,6- (Type 2) Eiermann GJ, Fisher MH, He H, dihydro[1,2,4]triazolo[4,3- Hickey GJ, Kowalchick JE, Leiting a]pyrazin- 7(8H)-yl]-1- B, Lyons K, Marsilio F, McCann (2,4,5- ME, Patel RA, Petrov A, Scapin G, trifluorophenyl)butan-2- Patel SB, Roy RS, Wu JK,. Wyvratt amine: A Potent, Orally MJ, Zhang BB, Zhu L, Thornberry Active Dipeptidyl NA, Weber AE. Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes Varenicline: An α4β2 CNS Coe JW, Brooks PR, Vetelino MG, 48(10), 3474- 481(2) Nicotinic Receptor Partial Wirtz MC, Arnold EP, Huang J, 3477 Agonist for Smoking Sands SB, Davis TI, Lebel LA, Fox Cessation CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley D, O'Neill BT. In Vitro and in Vivo Antitumor Scolaro C, Bergamo A, Brescacin 48(12), 4161- 367(3) Evaluation of L, Delfino R, Cocchietto M, 4171 Ruthenium(II)−Arene PTA Laurenczy G, Geldbach TJ, Sava G, Complexes Dyson PJ. Discovery and Preclinical Diabetes Augeri DJ, Robl JA, Betebenner 48(15), 5025- 327(4) Profile of Saxagliptin (BMS- (Type 2) DA, Magnin DR, Khanna A, 5037 477118): A Highly Potent, Robertson JG, Wang A, Simpkins Long-Acting, Orally Active LM, Taunk P, Huang Q, Han SP, Dipeptidyl Peptidase IV Abboa-Offei B, Cap M, Xin L, Tao L, Inhibitor for the Treatment Tozzo E, Welzel GE, Egan DM, of Type 2 Diabetes Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG. A Shape-Based 3-D Antibacteri Rush J. TS, Grant A, Mosyak L, 48(5), 1489– 314(5) Scaffold Hopping Method al Nicholls A. 1495 and Its Application to a Bacterial Protein−Protein Interaction Poly(amidoamine) Delivery Majoros IJ, Thomas TP, Mehta CB, 48(19), 5892- 282(6) Dendrimer-Based Baker JR. 5899 Multifunctional Engineered Nanodevice for Cancer Therapy Virtual Screening CNS Triballeau N, Acher F, Brabet I, Pin 48(7), 2534- 274(7) Workflow Development JP, Bertrand H-O. 2547 Guided by the “Receiver Operating Characteristic” Curve Approach. Application to High- 2

Throughput Docking on Metabotropic Glutamate Receptor Subtype 4 Discovery and Cocrystal Antitumor Grasberger BL, Lu T, Schubert C, 48(4), 909-912 271(8) Structure of Parks DJ, Carver TE, Koblish HK, Benzodiazepinedione Cummings MD, LaFrance LV, HDM2 Antagonists That Milkiewicz KL, Calvo RR, Maguire Activate p53 in Cells D, Lattanze J, Franks CF, Zhao S, Ramachandren K, Bylebyl GR, Zhang M, Manthey CL, Petrella EC, Pantoliano MW, Deckman IC, Spurlino JC, Maroney AC, Tomczuk BE, Molloy CJ, Bone, RF. Druggability Indices for Basic Hajduk PJ, Huth, JR, Fesik SW. 48(7), 2518- 268(9) Protein Targets Derived 2525 from NMR-Based Screening Data The PDBbind Database: Basic Wang R, Fang X, Lu Y, Yang CY, 48(12), 4111- 253(10) Methodologies and Wang S. 4119 Updates

2005: Perspectives Title Disease Authors Data Total area Cit. (Rank) Designed Multiple Ligands. Morphy R, Rankovic Z. 48(10), 6523- 462(1) An Emerging Drug 6543 Discovery Paradigm Neuronal Nicotinic Jensen AA, Frølund B, Liljefors T, 48(15), 4705- 354(2) Acetylcholine Receptors: Krogsgaard-Larsen P. 4745 Structural Revelations, Target Identifications, and Therapeutic Inspirations The Endocannabinoid Lambert DM, Fowler CJ. 48(16), 5059- 220(3) System: Drug Targets, Lead 5087 Compounds, and Potential Therapeutic Applications New Approaches toward De Clercq E. 48(5), 1297– 201(4) Anti-HIV Chemotherapy 1313 Adverse Cardiovascular Dogné J-M, Supuran CT, Pratico D. 48(7), 2251- 177(5) Effects of the Coxibs 2257

2006: Articles Title Disease Authors Data Total area Cit. (Rank) Extra Precision Glide: Basic Friesner RA, Murphy RB, Repasky 49(21), 6177– 915(1) Docking and Scoring MP, Frye LL, Greenwood JR, 6196 Incorporating a Model of Halgren TA, Sanschagrin PC, Mainz Hydrophobic Enclosure for DT. Protein−Ligand Complexes A Critical Assessment of Basic Warren GL, Andrews W, Capelli 49(20), 5912– 775(2) 3

Docking Programs and AM, Clarke B, LaLonde J, Lambert 5931 Scoring Functions MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS. Benchmarking Sets for Basic Huang N, Shoichet BK, Irwin JJ. 49(23), 6789– 580(3) Molecular Docking 6801 MolDock: A New Basic Thomsen R, Christensen MH. 49(11), 3315– 576(4) Technique for High- 3321 Accuracy Molecular Docking Novel Procedure for Basic Sherman W, Day T, Jacobson MP, 49(2), 534–553 568(5) Modeling Ligand/Receptor Friesner RA, Farid R. Induced Fit Effects Structure-Based Design of Antitumor Ding K, Lu Y, Nikolovska-Coleska Z, 49(12), 3432– 344(6) Spiro-oxindoles as Potent, Wang G, Qiu S, Shangary S, Gao 3435 Specific Small-Molecule W, Qin D, Stuckey J, Krajewski K, Inhibitors of the Roller PP, Wang S. MDM2−p53 Interacon

Antitumor Benzothiazoles. Antitumor Mortimer CG, Wells G, Crochard 49(1), 179–185 228(7) 26.1 2-(3,4- JP, Stone EL, Bradshaw TD, Dimethoxyphenyl)-5- Stevens MFG, Westwell AD. fluorobenzothiazole (GW 610, NSC 721648), a Simple Fluorinated 2- Arylbenzothiazole, Shows Potent and Selective Inhibitory Activity against Lung, Colon, and Breast Cancer Cell Lines Multivalent Effects of RGD Delivery Montet X, Funovics M, Montet- 49(20), 6087– 205(8) Peptides Obtained by Abou K, Weissleder R, Josephson 6093 Nanoparticle Display L. Novel HIV-1 Integrase Antiviral Sato M, Motomura T, Aramaki H, 49(5), 1506- 198(9) Inhibitors Derived from (HIV) Matsuda T, Yamashita M, Ito Y, 1508 Quinolone Antibiotics Kawakami H, Matsuzaki Y, Watanabe W, Yamataka K, Ikeda S, Kodama E, Matsuoka M, Shinkai H. Structure−Acvity Antitumor Habtemariam A, Melchart M, 49(23), 6858– 192(10) Relationships for Cytotoxic Fernández R, Parsons S, Oswald 6868 Ruthenium(II) Arene IDH, Parkin A, Fabbiani FPA, Complexes Containing Davidson JE, Dawson A, Aird RE, N,N-, N,O-, and O,O- Jodrell DI, Sadler PJ. Chelating Ligands

2006: Perspectives Title Disease Authors Data Total area Cit. (Rank) Prediction of Leach AR, Shoichet BK, Peishoff 49(20), 5851– 342(1) 4

Protein−Ligand CE. 5855 Interactions. Docking and Scoring: Successes and Gaps Medicinal Chemistry of Tron GC, Pirali T, Sorba G, Pagliai 49(11), 3033– 314(2) Combretastatin A4: F, Busacca S, Genazzani AA. 3044 Present and Future Directions Medicinal Chemistry of Jamieson C, Moir EM, Rankovic Z, 49(17), 5029– 202(3) hERG Optimizations: Wishart G. 5046 Highlights and Hang-Ups Structure−Brain Exposure Hitchcock SA, Pennington LD. 49(26), 7559– 182(4) Relationships 7583 Paclitaxel Prodrugs: Skwarczynski M, Hayashi Y, Kiso Y. 49(25), 7253– 89(5) Toward Smarter Delivery 7269 of Anticancer Agents

2007: Articles Title Disease Authors Data Total area Cit. a (Rank) Diverse, High-Quality Test Basic Hartshorn MJ, Verdonk ML, 50(4), 726–741 247(1) Set for the Validation of Chessari G, Brewerton SC, Mooij Protein−Ligand Docking WTM, Mortenson PN, Murray CW. Performance

Comparison of Shape- Basic Hawkins PCD, Skillman AG, 50(1), 74–82 242(2) Matching and Docking as Nicholls A. Virtual Screening Tools Discovery of Alogliptin: A Diabetes Jun F, Zhiyuan Z, Wallace MB, 50(10), 2297– 200(3) Potent, Selective, (Type 2) Stafford JA, Kaldor SW, Kassel DB, 2300 Bioavailable, and Navre M, Shi L, Skene RJ, Asakawa Efficacious Inhibitor of T, Takeuchi K, Xu R, Webb DR, Dipeptidyl Peptidase IV Gwaltney SL. Discovery of 1-(4- Cardiovasc Pinto DJP, Orwat MJ, Koch S, Rossi 50(22), 5339- 194(4) Methoxyphenyl)-7-oxo-6- ular KA, Alexander RS, Smallwood A, 5356 (4-(2-oxopiperidin-1- (anticoagul Wong PC, Rendina AR, Luettgen yl)phenyl)-4,5,6,7- ant) JM, Knabb RM, He K, Xin B, Wexler tetrahydro- 1H- RR, Lam PYS. pyrazolo[3,4-c]pyridine-3- carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa A High-Throughput Screen Basic Feng BY, Simeonov A, Jadhav A, 50(10), 2385– 157(5) for Aggregation-Based Babaoglu K, Inglese J, Shoichet BK, 2390 Inhibition in a Large Austin CP. Compound Library Studies Leading to Potent, Antitumor Bruncko M, Oost TK, Belli BA, Ding 50(4), 641–662 151(6) 5

Dual Inhibitors of Bcl-2 and H, Joseph MK, Kunzer A, Bcl-xL Martineau D, McClellan WJ, Mitten M, Ng SC, Nimmer PM, Oltersdorf T, Park CM, Petros AM, Shoemaker AR, Song X, Wang X, Wendt MD, Zhang H, Fesik SW, Rosenberg SH, Elmore SW. Discovery, Synthesis, and Antitumor Mortlock AA, Foote KM, Heron 50(9), 2213– 149(7) in Vivo Activity of a New NM, Jung FH, Pasquet G, Lohmann 2224 Class of JJM, Warin N, Renaud F, Savi CD, Pyrazoloquinazolines as Roberts NJ, Johnson T, Dousson Selective Inhibitors of CB, Hill GB, Perkins D, Hatter G, Aurora B Kinase Wilkinson RW, Wedge SR, Heaton SP, Odedra R, Keen NJ, Crafter C, Brown E, Thompson K, Brightwell S, Khatri L, Brady MC, Kearney S, McKillop D, Rhead S, Parry T, Green S. Stabilization of G- Antitumor Ou TM, Lu YJ, Zhang C, Huang ZS, 50(7), 1465– 148(8) Quadruplex DNA and Wang XD, Tan JH, Chen Y, Ma DL, 1474 Down-Regulation of Wong KY, Tang JCO, Chan ASC, Gu Oncogene c-myc by LQ. Quindoline Derivatives Molecular Dynamics and Antiviral Hou T, Yu R. 50(6), 1177– 134(9) Free Energy Studies on the (HIV) 1188 Wild-type and Double Mutant HIV-1 Protease Complexed with Amprenavir and Two Amprenavir-Related Inhibitors: Mechanism for Binding and Drug Resistance 8-(3-(R)-Aminopiperidin-1- Diabetes Eckhardt M, , Langkopf E, , Mark 50(26), 6450– 131(10) yl)-7-but-2-ynyl-3-methyl- (Type 2) M, Tadayyon M, Thomas L, Nar H, 6453 1-(4-methyl-quinazolin-2- Pfrengle W, Guth B, Lotz R, Sieger ylmethyl)-3,7- P, Fuchs H, Himmelsbach F. dihydropurine-2,6-dione (BI 1356), a Highly Potent, Selective, Long-Acting, and Orally Bioavailable DPP-4 Inhibitor for the Treatment of Type 2 Diabetes Application of Fragment- CNS Edwards PD, Albert JS, Sylvester 50(24), 5912– 131(10) Based Lead Generation to M, Aharony D, Andisik D, 5925 the Discovery of Novel, Callaghan O, Campbell JB, Carr RA, Cyclic Amidine β-Secretase Chessari G, Congreve M, Inhibitors with Nanomolar Frederickson M, Folmer RHA, Potency, Cellular Activity, Geschwindner S, Koether G, and High Ligand Efficiency Kolmodin K, Krumrine J, Mauger RC, Murray CW, Olsson LL, Patel S, Spear N, Tian G. 6

Structures of Human CNS Binda C, Wang J, Pisani L, Caccia C, 50(23), 5848– 131(10) Monoamine Oxidase B Carotti A, Salvati P, Edmondson 5852 Complexes with Selective DE, Mattevi A. Noncovalent Inhibitors: Safinamide and Coumarin Analogs

2007: Perspectives Title Disease Authors Data Total area Cit. (Rank) Molecular Recognition of Liao JJL. 50(3), 409–424 270(1) Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors Basis for Design and Hall MD, Mellor HR, Callaghan R, 50(15), 3403– 172(2) Development of Hambley TW. 3411 Platinum(IV) Anticancer Complexes Structural and Functional Blobaum AL, Marnett LJ. 50(7), 1425– 125(3) Basis of Cyclooxygenase 1441 Inhibition Advances in Development Zhang A, Zhang Y, Branfman AR, 50(4), 171–181 63(4) of Dopaminergic Baldessarini RJ, Neumeyer JL. Aporphinoids N-Methyl-D-Aspartate Childers WE, Baudy RB. 50(11), 2557– 55(5) Antagonists and 2562 Neuropathic Pain: The Search for Relief

2008: Articles Title Disease Authors Data Total area Cit. (Rank) The Identification of 2-(1H- Antitumor Folkes AJ, Ahmadi K, Alderton WK, 51(18), 5522– 342(1) Indazol-4-yl)-6-(4- Alix S, Baker SJ, Box G, 5532 methanesulfonyl- Chuckowree IS, Clarke Depledge P, piperazin-1-ylmethyl)-4- Eccles SA, Friedman LS, Hayes A, morpholin-4-yl-thieno[3,2- Hancox TC, Kugendradas A, d]pyrimidine (GDC-0941) Lensun L, Moore P, Olivero AG, as a Potent, Selective, Pang J, Patel S, Pergl-Wilson GH, Orally Bioavailable Raynaud FI, Robson A, Saghir N, Inhibitor of Class I PI3 Salphati L, Sohal S, Ultsch MH, Kinase for the Treatment Valenti M, Wallweber HJA, Chi of Cancer Wan N, Wiesmann C, Workman P, Zhyvoloup A, Zvelebil MJ, Shuttleworth SJ. Generation of a Set of Basic Gleeson MP. 51(4), 817–834 316(2) Simple, Interpretable ADMET Rules of Thumb Discovery of Raltegravir, a Antiviral Summa V, Petrocchi A, Bonelli F, 51(2), 5843– 264(3) 7

Potent, Selective Orally (HIV) Crescenzi B, Donghi M, Ferrara M, 5855 Bioavailable HIV-Integrase Fiore F, Gardelli C, Paz OG, Hazuda Inhibitor for the Treatment DJ, Jones P, Kinzel O, Laufer R, of HIV-AIDS Infection Monteagudo E, Muraglia E, Nizi E, Orvieto F, Pace P, Pescatore G, Scarpelli R, Stillmock K, Witmer MV, Rowley M. Discovery of Dapagliflozin: Diabetes Meng W, Ellsworth BA, Nirschl AA, 51(5), 1145– 218(4) A Potent, Selective Renal (Type 2) McCann PJ, Patel M, Girotra RN, 1149 Sodium-Dependent Wu G, Sher PM, Morrison EP, Glucose Cotransporter 2 Biller SA, Zahler R, Deshpande PP, (SGLT2) Inhibitor for the Pullockaran A, Hagan DL, Morgan Treatment of Type 2 N, Taylor JR, Obermeier MT, Diabetes Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN. 4,5-Diarylisoxazole Hsp90 Antitumor Brough PA, Aherne W, Barril X, 51(2), 196–218 199(5) Chaperone Inhibitors: Borgognoni J, Boxall K, Cansfield Potential Therapeutic JE, Cheung KMJ, Collins I, Davies Agents for the Treatment NGM, Drysdale MJ, Dymock B, of Cancer Eccles SA, Finch H, Fink A, Hayes A, Howes R, Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E, Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A, Walmsley DL, Webb P, Wood M, Workman P, Wright L. 4-[3-(4- Antitumor Menear KA, Adcock C, Boulter R, 51(20), 6581– 158(6) Cyclopropanecarbonylpipe Cockcroft XL, Copsey L, Cranston 6591 razine-1-carbonyl)-4- A, Dillon KJ, Drzewiecki J, Garman fluorobenzyl]-2H- S, Gomez S, Javaid H, Kerrigan F, phthalazin-1-one: A Novel Knights C, Lau A, Loh VM, Bioavailable Inhibitor of Matthews ITW, Moore S, Poly(ADP-ribose) O’Connor MJ, Smith GCM, Martin Polymerase-1 NMB. Identification of N-(4- Antitumor Wyatt PG, Woodhead AJ, Berdini 51(16), 4986– 144(7) Piperidinyl)-4-(2,6- V, Boulstridge JA, Carr MG, Cross 4999 dichlorobenzoylamino)-1H- DM, Davis DJ, Devine LA, Early TR, pyrazole-3-carboxamide Feltell RE, E. Lewis J, McMenamin (AT7519), a Novel Cyclin RL, Navarro EF, O’Brien MA, Dependent Kinase O’Reilly M, Reule M, Saxty G, Inhibitor Using Fragment- Seavers LCA, Smith DM, Squires Based X-Ray MS, Trewartha G, Walker MT, Crystallography and Woolford AJA. Structure Based Drug Design Emerging Protein Targets Antitumor Casini A, Gabbiani C, Sorrentino F, 51(21), 6773– 134(8) for Anticancer Rigobello MP, Bindoli A, Geldbach 6781 8

Metallodrugs: Inhibition of TJ, Marrone A, Re N, Hartinger CG, Thioredoxin Reductase and Dyson PJ, Messori L. Cathepsin B by Antitumor Ruthenium(II)−Arene Compounds Ensemble-Based Virtual Antiviral Cheng LS, Amaro RE, Xu D, Li WW, 51(13), 3878– 131(9) Screening Reveals Arzberger PW, McCammon JA. 3894 Potential Novel Antiviral Compounds for Avian Influenza Neuraminidase Discovery of a Novel, Cardiovasc Chackalamannil S, Wang Y, 51(11), 3061– 128(10) Orally Active Himbacine- ular Greenlee WJ, Hu Z, Xia Y, Ahn HS, 3064 Based Thrombin Receptor (anticoagul Boykow G, Hsieh Y, Palamanda J, Antagonist (SCH 530348) ant) Agans-Fantuzzi J, Kurowski S, with Potent Antiplatelet Graziano M, Chintala M. Activity

2008: Perspectives Title Disease Authors Data Total area Cit. (Rank) The Many Roles for Hagmann WK. 51(15), 4359– 892(1) Fluorine in Medicinal 4369 Chemistry Recent Developments in Congreve M, Chessari G, Tisi D, 51(13), 3661– 357(2) Fragment-Based Drug Woodhead AJ. 3680 Discovery Multi-target-Directed Cavalli A, Bolognesi Ml, Minarini 51(3), 347–372 342(3) Ligands To Combat A, Rosini M, Tumiatti V, Recanatini Neurodegenerative M, Melchiorre C. Diseases

Natural Products as Leads Newman DJ. 51(9), 2589– 281(4) to Potential Drugs: An Old 2599 Process or the New Hope for Drug Discovery? Histone Deacetylase Paris M, Porcelloni M, Binaschi M, 51(6), 1505– 208(5) Inhibitors: From Bench to Fattori D. 1529 Clinic

2009: Articles Title Disease Authors Data Total area Cit. (Rank) Escape from Flatland: Basic Lovering F, Bikker J, Humblet C. 52(21), 6752– 413(1) Increasing Saturation as an 6756 Approach to Improving Clinical Success Fragment-Based Discovery Antitumor Howard S, Berdini V, Boulstridge 52(2), 379–388 162(2) of the Pyrazol-4-yl Urea JA, Carr MG, Cross DM, Curry J, (AT9283), a Multitargeted Devine LA, Early TR, Fazal L, Gill Kinase Inhibitor with AL, Heathcote M, Maman S, 9

Potent Aurora Kinase Matthews JE, McMenamin RL, Activity Navarro EF, O’Brien MA, O’Reilly M, Rees DC, Reule M, Tisi D, Williams G, Vinković M, Wyatt PG. Discovery of a Potent and Antitumor Tremblay MR, Lescarbeau A, 52(14), 4400– 126(3) Orally Active Hedgehog Grogan MJ, Tan E, Lin G, Austad 4418 Pathway Antagonist (IPI- BC, Yu LC, Behnke ML, Nair SJ, 926) Hagel M, White K, Conley J, Manna JD, Alvarez-Diez TM, Hoyt J, Woodward CN, Sydor JR, Pink M, MacDougall J, Campbell MJ, Cushing J, Ferguson J, Curtis MS, McGovern K, Read MA, Palombella VJ, Adams J, Castro AC. The Importance of Antitumor Sun D, Hurley LH. 52(9), 2863– 119(4) Negative Superhelicity in 2874 Inducing the Formation of G-Quadruplex and i-Motif Structures in the c-Myc Promoter: Implications for Drug Targeting and Control of Gene Expression Discovery of a Novel Class CNS Verhoest PR, Chapin DS, Corman 52(16), 5188– 114(5) of Phosphodiesterase 10A M, Fonseca K, Harms JF, Hou X, 5196 Inhibitors and Marr ES, Menniti FS, Nelson F, Identification of Clinical O’Connor R, Pandit J, Proulx- Candidate 2-[4-(1-Methyl- LaFrance C, Schmidt AW, Schmidt 4-pyridin-4-yl-1H-pyrazol- CJ, Suiciak JA, Liras S. 3-yl)-phenoxymethyl]- quinoline (PF-2545920) for the Treatment of Schizophrenia Heteroaromatic Rings of Basic Pitt WR, Parry DM, Perry BG, 52(9), 2952– 113(6) the Future Groom CR, 2963 Design and Synthesis of an Antitumor Zhou HJ, Aujay MA, Bennett MK, 52(9), 3028– 109(7) Orally Bioavailable and Dajee M, Demo SD, Fang Y, Ho 3038 Selective Peptide MN, Jiang J, Kirk CJ, Laidig GJ, Epoxyketone Proteasome Lewis ER, Lu Y, Muchamuel T, Inhibitor (PR-047) Parlati F, Ring E, Shenk KD, Shields J, Shwonek PJ, Stanton T, Sun CM, Sylvain C, Woo TM, Yang J. Discovery of the Poly(ADP- Antitumor Penning TD, Zhu GD, Gandhi VB, 52(2), 514–523 108(8) ribose) Polymerase (PARP) Gong J, Liu X, Shi Y, Klinghofer V, Inhibitor 2-[(R)-2- Johnson EF, Donawho CK, Frost methylpyrrolidin-2-yl]-1H- DJ, Bontcheva-Diaz V, Bouska JJ, benzimidazole-4- Osterling DJ, Olson AM, Marsh KC, carboxamide (ABT-888) for Luo Y, Giranda VL. the Treatment of Cancer Halogen Bonding—A Novel Basic Lu Y, Shi T, Wang Y, Yang H, Yan X, 52(9), 2854– 106(9) Interaction for Rational Luo X, Jiang H, Zhu W. 2862 Drug Design? 10

Novel Chemical Space Basic Rosén J, Gottfries J, Muresan S, 52(7), 1953– 100(10) Exploration via Natural Backlund A, Oprea TI. 1962 Products

2009: Perspectives Title Disease Authors Data Total area Cit. (Rank) Covalent Modifiers: An Potashman MH, Duggan ME. 52(14), 1231– 126(1) Orthogonal Approach to 1246 Drug Design Thiosemicarbazones from Yu Y, Kalinowski DS, Kovacevic Z, 52(17), 5271– 120(2) the Old to New: Iron Siafakas AR, Jansson PJ, Stefani C, 5294 Chelators That Are More Lovejoy DB, Sharpe PC, Bernhardt Than Just Ribonucleotide PV, Richardson DR. Reductase Inhibitors Discovery and Pollard JR, Mortimore M. 52(9), 2629– 106(3) Development of Aurora 2651 Kinase Inhibitors as Anticancer Agents Neglected Tropical Cavalli A, Bolognesi ML. 52(23), 7339– 100(4) Diseases: Multi-Target- 7359 Directed Ligands in the Search for Novel Lead Candidates against Trypanosoma and Leishmania The pKBHX Database: Laurence C, Brameld KA, Graton J, 52(14), 4073– 96(5) Toward a Better Le Questel JY, Renault E. 4086 Understanding of Hydrogen-Bond Basicity for Medicinal Chemists

2010: Articles Title Disease Authors Data Total area Cit. a (Rank) New Substructure Filters Basic Baell JB, Holloway GA. 53(7), 2719– 363(1) for Removal of Pan Assay 2740 Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays Spirotetrahydro β- Antiparasiti Yeung BKS, Zou B, Rottmann M, 53(14), 5155– 130(2) Carbolines c Lakshminarayana SB, Ang SH, 5164 (Spiroindolones): A New Leong SY, Tan J, Wong J, Keller- Class of Potent and Orally Maerki, Fischli S, Goh A, Schmitt Efficacious Compounds for EK, Krastel P, Francotte E, Kuhen the Treatment of Malaria K, Plouffe D, Henson K, Wagner T, Winzeler EA, Petersen F, Brun R, Dartois V, Diagana TT, Keller TH. Discovery of a β-d-2′- Antiviral Sofia MJ, Bao D, Chang W, Du J, 53(19), 7202– 122(3) 11

Deoxy-2′-α-fluoro-2′-β-C- (HCV) Nagarathnam D, Rachakonda S, 7218 methyluridine Nucleotide Reddy PG, Ross BS, Wang P, Zhang Prodrug (PSI-7977) for the HR, Bansal S, Espiritu C, Keilman Treatment of Hepatitis C M, Lam AM, Micolochick Steuer Virus HM, Niu C, Otto MJ, Furman PA. Deciphering the Not Maresca A, Temperini C, Pochet L, 53(1), 335–344 119(4) Mechanism of Carbonic specified Masereel B, Scozzafava A, Anhydrase Inhibition with Supuran CT. Coumarins and Thiocoumarins Structure-Based Discovery Not Katritch V, Jaakola VP, Lane JR, Lin 53(4), 1799– 109(5) of Novel Chemotypes for specified J, IJzerman AP, Yeager M, 1809 Adenosine A2A Receptor Kufareva I, Stevens RC, Abagyan R. Antagonists Benzimidazol-2-ylidene Antitumor Rubbiani R, Kitanovic I, Alborzinia 53(24), 8608– 108(6) Gold(I) Complexes Are H, Can S, Kitanovic A, Onambele 8618 Thioredoxin Reductase LA, Stefanopoulou M, Geldmacher Inhibitors with Multiple Y, Sheldrick WS, Wolber G, Prokop Antitumor Properties A, Wölfl S, Ingo Ott I. Discovery of the Dual CNS Cox CD, Breslin MJ, Whitman DB, 53(14), 5320– 107(7) Orexin Receptor Schreier JD, McGaughey GB, 5332 Antagonist [(7R)-4-(5- Bogusky MJ, Roecker AJ, Mercer Chloro-1,3-benzoxazol-2- SP, Bednar RA, Lemaire W, Bruno yl)-7-methyl-1,4-diazepan- JG, Reiss DR, C. Harrell M, Murphy 1-yl][5-methyl-2-(2H-1,2,3- KL, Garson SL, Doran SM, triazol-2- Prueksaritanont T, Anderson WB, yl)phenyl]methanone (MK- Tang C, Roller S, Cabalu TD, Cui D, 4305) for the Treatment of Hartman GD, Young SD, Koblan Insomnia KS, Winrow CJ, Renger JJ, Coleman PJ. Structure-Based Discovery Not Carlsson J, Yoo L, Gao ZG, Irwin JJ, 53(9), 3748– 107(7) of A2A Adenosine specified Shoichet BK, Jacobson KA. 3755 Receptor Ligands Discovery of Canagliflozin, Diabetes Nomura S, Sakamaki S, Hongu M, 53(17), 6355– 106(8) a Novel C-Glucoside with (Type 2) Kawanishi E, Koga Y, Sakamoto T, 6360 Thiophene Ring, as Yamamoto Y, Ueta K, Kimata H, Sodium-Dependent Nakayama K, Tsuda-Tsukimoto M. Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus Oxetanes in Drug Basic Wuitschik G, Carreira EM, Wagner 53(8), 3227– 99(9) Discovery: Structural and B, Fischer H, Parrilla I, Schuler F, 3246 Synthetic Insights Rogers-Evans M, Müller K. In Vitro and In Vivo Photodyna Lim SH, Thivierge C, Nowak- 53(7), 2865– 91(10) Photocytotoxicity of Boron mic Sliwinska P, Han J, van den Bergh 2874 Dipyrromethene therapy H, Wagnières G, Burgess K, Lee Derivatives for HB. Photodynamic Therapy An Analysis of the Binding Basic Perola E. 53(7), 2986– 91(10) Efficiencies of Drugs and 2997 Their Leads in Successful Drug Discovery Programs 12

2010: Perspectives Title Disease Authors Data Total area Cit. (Rank) A Medicinal Chemist’s Bissantz C, Kuhn B, Stahl M. 53(14), 5061– 377(1) Guide to Molecular 5084 Interactions Twenty-Six Years of Anti- Mehellou Y, De Clercq E. 53(2), 521–538 176(2) HIV Drug Discovery: Where Do We Stand and Where Do We Go? Nitrile-Containing Fleming FF, Yao L, Ravikumar PC, 53(22), 7902– 155(3) Pharmaceuticals: Funk L, Shook BC. 7917 Efficacious Roles of the Nitrile Pharmacophore Through the “Gatekeeper Zuccotto F, Ardini E, Casale E, 53(7), 2681– 155(3) Door”: Exploiting the Angiolini M. 2694 Active Kinase Conformation Folate-Targeted Therapies Xia W, Low PS. 53(7), 6811– 152(4) for Cancer 6824 Heat Shock Protein 70 Evans CG, , Chang L, Gestwicki JE. 53(12), 4585- 139(5) (Hsp70) as an Emerging 4602 Drug Target

2011: Articles Title Disease Authors Data Total area Cit. a (Rank) Structure Based Drug Antitumor Cui JJ, Tran-Dubé M, Shen H, 54(18), 6342– 187(1) Design of Crizotinib (PF- Nambu M, Kung PP, Pairish M, Jia 6363 02341066), a Potent and L, Meng J, Funk L, Botrous I, Selective Dual Inhibitor of McTigue M, Grodsky N, Ryan K, Mesenchymal–Epithelial Padrique E, Alton G, Timofeevski Transition Factor (c-MET) S, Yamazaki S, Li Q, Zou H, Kinase and Anaplastic Christensen J, Mroczkowski B, Lymphoma Kinase (ALK) Bender S, Kania RS, Edwards MP. Discovery of 1-[2-(2,4- CNS Bang-Andersen B, Ruhland T, 54(9), 3206– 119(2) Dimethylphenylsulfanyl)ph Jørgensen M, Smith G, 3221 enyl]piperazine (Lu Frederiksen K, Jensen KG, Zhong AA21004): A Novel H, Nielsen SM, Hogg S, Mørk A, Multimodal Compound for Stensbøl TB. the Treatment of Major Depressive Disorder Ureido-Substituted Antitumor Pacchiano F, Carta F, McDonald 54(6), 1896– 109(3) Benzenesulfonamides PC, Lou Y, Vullo D, Scozzafava A, 1902 Potently Inhibit Carbonic Dedhar S, Supuran CT. Anhydrase IX and Show Antimetastatic Activity in a Model of Breast Cancer Metastasis 13

Discovery and Not Chung C, Coste H, White JH, 54(11), 3827– 100(4) Characterization of Small specified Mirguet O, Wilde J, Gosmini RL, 3838 Molecule Inhibitors of the Delves C, Magny SM, Woodward BET Family Bromodomains R, Hughes SA, Boursier EV, Flynn H, Bouillot AM, Bamborough P, Brusq JMG, Gellibert FJ, Jones EJ, Riou AM, Homes P, Martin SL, Uings IJ, Toum J, Clément CA, Boullay AB, Grimley RL, Blandel FM, Prinjha RK, Lee K, Kirilovsky J, Nicodeme E. N-Fused Imidazoles As Antitumor Baviskar AT, Madaan C, Preet R, 54(14), 5013– 80(5) Novel Anticancer Agents Mohapatra P, Jain V, Agarwal A, 5030 That Inhibit Catalytic Guchhait SK, Kundu CN, Banerjee Activity of Topoisomerase UC, Bharatam PV. IIα and Induce Apoptosis in G1/S Phase Organometallic Antitumor Nowak-Sliwinska P, van Beijnum 54(11), 3895– 80(5) Ruthenium(II) Arene JR, Casini A, Nazarov AA, 3902 Compounds with Wagnières G, van den Bergh H, Antiangiogenic Activity Dyson PJ, Griffioen AW. Discovery and SAR of 5-(3- Antitumor Pierre F, Chua PC, O’Brien SE, 54(2), 635–654 77(6) Chlorophenylamino)benzo[ Siddiqui-Jain A, Bourbon P, c][2,6]naphthyridine-8- Haddach M, Michaux J, Nagasawa carboxylic Acid (CX-4945), J, Schwaebe MK, Stefan E, the First Clinical Stage Vialettes A, Whitten JP, Chen TK, Inhibitor of Protein Kinase Darjania L , Stansfield R, Anderes CK2 for the Treatment of K, Bliesath J, Drygin D, Ho C, Cancer Omori M, Proffitt C, Streiner N, Trent K, Rice WG, Ryckman DM. Structure-Guided Lead Antiparasiti Coteron JM, Marco M, Esquivias J, 54(15), 5540– 76(7) Optimization of c Deng X, White KL, White J, Koltun 5561 Triazolopyrimidine-Ring M, El Mazouni F, Kokkonda S, Substituents Identifies Katneni K, Bhamidipati R, Potent Plasmodium Shackleford DM, Angulo-Barturen falciparum Dihydroorotate I, Ferrer SDB, Jiménez-Díaz MB, Dehydrogenase Inhibitors Gamo FJ, Goldsmith EJ, Charman with Clinical Candidate WN, Bathurst I, Floyd D, Potential Matthews D, Burrows JN, Rathod PK, Charman SA, Phillips MA. Discovery of 3-(2,6- Antitumor Guagnano V, Furet P, Spanka C, 54(20), 7066– 75(8) Dichloro-3,5-dimethoxy- Bordas V, Le Douget M, Stamm C, 7083 phenyl)-1-{6-[4-(4-ethyl- Brueggen J, Jensen MR, Schnell C, piperazin-1-yl)- Schmid H, Wartmann M, phenylamino]-pyrimidin-4- Berghausen J, Drueckes P, yl}-1-methyl-urea (NVP- Zimmerlin A, Bussiere D, Murray J, BGJ398), A Potent and Porta DG. Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine Kinase Crystal Structure-Based Antiallergy de Graaf C, Kooistra AJ, Vischer 54(23), 8195– 72(9) 14

Virtual Screening for HF, Katritch V, Kuijer M, Shiroishi 8206 Fragment-like Ligands of M, Iwata S, Shimamura T, Stevens the Human Histamine H1 RC, de Esch IJP, Leurs R. Receptor Comparative in Vitro Antitumor Rubbiani R, Can S, Kitanovic I, 54(24), 8646– 71(10) Evaluation of N- Alborzinia H, Stefanopoulou M, 8657 Heterocyclic Carbene Kokoschka M, Mönchgesang S, Gold(I) Complexes of the Sheldrick WS, Wölfl S, Ott I. Benzimidazolylidene Type

2011: Perspectives Title Disease Authors Data Total area Cit. a (Rank) Organometallic Anticancer Gasser G, Ott I, Metzler-Nolte N. 54(1), 3–25 450(1) Compounds Synopsis of Some Recent Meanwell NA. 54(8), 2529– 360(2) Tactical Application of 2591 Bioisosteres in Drug Design The Medicinal Chemist’s Roughley SD, Jordan AM. 54(10), 3451– 274(3) Toolbox: An Analysis of 3479 Reactions Used in the Pursuit of Drug Candidates Macrocycles Are Great Marsault E, Peterson ML. 54(7), 1961– 159(4) Cycles: Applications, 2004 Opportunities, and Challenges of Synthetic Macrocycles in Drug Discovery Remarkable Potential of Mucha A, Kafarski P, Berlicki L. 54(17), 5955– 108(5) the α- 5980 Aminophosphonate/Phosp hinate Structural Motif in Medicinal Chemistry Improvement in Aqueous Ishikawa M, Hashimoto Y. 54(6), 1539- 108(5) Solubility in Small 1554 Molecule Drug Discovery Programs by Disruption of Molecular Planarity and Symmetry

2012: Articles Title Disease Authors Data Total area Cit. a (Rank) Directory of Useful Decoys, Basic Mysinger MM, Carchia M, Irwin JJ, 55(14), 6582– 97(1) Enhanced (DUD-E): Better Shoichet BK. 6594 Ligands and Decoys for Better Benchmarking Discovery of 1,2,4-Triazine CNS Congreve M, Andrews SP, Doré 55(5), 1898– 96(2) Derivatives as Adenosine AS, Hollenstein K, Hurrell E, 1903 A2A Antagonists using Langmead CJ, Mason JS, Ng IW, 15

Structure Based Drug Tehan B, Zhukov A, Weir M, Design Marshall FH. Oxadiazoles in Medicinal Basic Boström J, Hogner A, Llinàs A, 55(5), 1817– 82(3) Chemistry Wellner E, Plowright AT 1830 Discovery of 7-Methyl-5- Antitumor Axten JM, Medina JR, Feng Y, Shu 55(16), 7193– 76(4) (1-{[3- A, Romeril SP, Grant SW, Li WHH, 7207 (trifluoromethyl)phenyl]ac Heerding DA, Minthorn E, etyl}-2,3-dihydro-1H-indol- Mencken T, Atkins C, Liu Q, 5-yl)-7H-pyrrolo[2,3- Rabindran S, Kumar R, Hong X, d]pyrimidin-4-amine Goetz A, Stanley T, Taylor JD, (GSK2606414), a Potent Sigethy SD, Tomberlin GH, Hassell and Selective First-in-Class AM, Kahler KM, Shewchuk LM, Inhibitor of Protein Kinase Gampe RT. R (PKR)-like Endoplasmic Reticulum Kinase (PERK) New Tacrine–4-Oxo-4H- CNS Fernández-Bachiller MI, Pérez C, 55(3), 1303– 70(5) chromene Hybrids as Monjas L, Rademann J, Rodríguez- 1317 Multifunctional Agents for Franco MI. the Treatment of Alzheimer’s Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties Fragment-Based Discovery Antiinflam Bamborough P, Diallo H, Goodacre 55(2), 587–596 68(6) of Bromodomain Inhibitors matory JD, Gordon L, Lewis A, Seal JT, Part 2: Optimization of Wilson DM, Woodrow MD, Chung Phenylisoxazole C. Sulfonamides Structure-Based Design of Antitumor Rew Y, Sun D, Gonzalez-Lopez De 55(11), 4936– 64(7) Novel Inhibitors of the Turiso F, Bartberger MD, Beck HP, 4954 MDM2–p53 Interaction Canon J, Chen A, Chow D, Deignan J, Fox BM, Gustin D, Huang X, Jiang M, Jiao X, Jin L, Kayser F, Kopecky DJ, Li Y, Lo MC, Long AM, Michelsen K, Oliner JD, Osgood T, Ragains M, Saiki AY, Schneider S, Toteva M, Yakowec P, Yan X, Ye Q, Yu D, Zhao X, Zhou J, Medina JC, Olson SH. Gold(I) Carbene Complexes Antitumor Schuh E, Pflüger C, Citta A, Folda 55(11), 5518- 63(8) Causing Thioredoxin 1 and A, Rigobello MP, Bindoli A, Casini 5528 Thioredoxin 2 Oxidation as A, Mohr F. Potential Anticancer Agents Classification of Inhibitors Delivery Karlgren M, Vildhede A, Norinder 55(10), 4740– 63(8) of Hepatic Organic Anion U, Wisniewski JR, Kimoto E, Lai Y, 4763 Transporting Polypeptides Haglund U, Artursson P. (OATPs): Influence of Protein Expression on Drug–Drug Interactions Fragment-Based Discovery Antiinflam Chung C, Dean AW, Woolven JM, 55(2), 576–586 61(9) of Bromodomain Inhibitors matory Bamborough P. 16

Part 1: Inhibitor Binding Modes and Implications for Lead Discovery Dithiocarbamates Strongly Glaucoma Carta F, Aggarwal M, Maresca A, 55(4), 1721– 60(10) Inhibit Carbonic Scozzafava A, McKenna R, Masini 1730 Anhydrases and Show E, Supuran CT. Antiglaucoma Action in Vivo

2012: Perspectives Title Disease Authors Data Total area Cit. a (Rank) Nucleoside, Nucleotide, Sofia MJ, Chang W, Furman PA, 55(6), 2481– 87(1) and Non-Nucleoside Mosley RT, Ross BS. 2531 Inhibitors of Hepatitis C Virus NS5B RNA- Dependent RNA- Polymerase Allosteric Modulation of Melancon BJ, Hopkins CR, Wood 55(4), 1445– 86(2) Seven Transmembrane MR, Emmitte KA, Niswender CM, 1464 Spanning Receptors: Christopoulos A, Conn PJ, Lindsley Theory, Practice, and CW. Opportunities for Central Nervous System Drug Discovery Charting, Navigating, and Lachance H, Wetzel S, Kumar K, 55(13), 5989– 85(3) Populating Natural Product Waldmann H. 6001 Chemical Space for Drug Discovery Exploring Activity Cliffs in Stumpfe D, Bajorath J. 55(7), 2932– 85(3) Medicinal Chemistry 2942 Continuous Flow Synthesis. Malet-Sanz L, Susanne F. 55(9), 4062– 80(4) A Pharma Perspective 4098 Modern Phenotypic Drug Lee JA, Uhlik MT, Moxham CM, 55(10), 4527– 60(5) Discovery Is a Viable, Tomandl D, Sall DJ. 4538 Neoclassic Pharma Strategy

2013: Articles Title Disease Authors Data Total area Cit. a (Rank) Synthesis, Structure– Antitumor Marsilje TH, Pei W, Chen B, Lu W, 56(14), 5675– 59(1) Activity Relationships, and Uno T, Jin Y, Jiang T, Kim S, Li N, 5690 in Vivo Efficacy of the Warmuth M, Sarkisova Y, Sun F, Novel Potent and Selective Steffy A, Pferdekamper AMC, Li Anaplastic Lymphoma AG, Joseph SB, Kim Y, Liu B, Kinase (ALK) Inhibitor 5- Tuntland T, Cui X, Gray NS, Chloro-N2-(2-isopropoxy- Steensma R, Wan Y, Jiang J, 5-methyl-4-(piperidin-4- Chopiuk G, Li J, Gordon WP, yl)phenyl)-N4-(2- Richmond W, Johnson K, Chang J, 17

(isopropylsulfonyl)phenyl) Groessl T, He YQ, Phimister A, pyrimidine-2,4-diamine Aycinena A, Lee CC, Bursulaya B, (LDK378) Currently in Karanewsky DS, Seidel HM, Harris Phase 1 and Phase 2 JL, Michellys PY. Clinical Trials Discovery of Potent Antitumor Friberg A, Vigil D, Zhao B, Daniels 56(1), 15–30 53(2) Myeloid Cell Leukemia 1 RN, Burke JP, Garcia-Barrantes (Mcl-1) Inhibitors Using PM, Camper D, Chauder BA, Lee T, Fragment-Based Methods Olejniczak ET, Fesik SW. and Structure-Based Design Discovery of RG7388, a Antitumor Ding Q, Zhang Z, Liu JJ, Jiang N, 56(14), 5979– 51(3) Potent and Selective p53– Zhang J, Ross TM, Chu XJ, 5983 MDM2 Inhibitor in Clinical Bartkovitz D, Podlaski F, Janson C, Development Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassilev LT, Graves B. A Potent Small-Molecule Antitumor Zhao Y, Yu S, Sun W, Liu L, Lu J, 56(13), 5553– 47(4) Inhibitor of the MDM2– McEachern D, Shargary S, Bernard 5561 p53 Interaction (MI-888) D, Li X, Zhao T, Zou P, Sun D, Wang Achieved Complete and S. Durable Tumor Regression in Mice Discovery of Thieno[3,2- Not Disch JS, Evindar G, Chiu CH, Blum 56(9), 3666– 47(4) d]pyrimidine-6- specified CA, Dai H, Jin L, Schuman E, Lind 3679 carboxamides as Potent KE, Belyanskaya SL, Deng J, Coppo Inhibitors of SIRT1, SIRT2, F, Aquilani L, Graybill TL, Cuozzo and SIRT3 JW, Lavu S, Mao C, Vlasuk GP, Perni RB. Biophysical Fragment Not Christopher JA, Brown J, Doré AS, 56(9), 3446– 41(5) Screening of the β1- specified Errey JC, Koglin M, Marshall FH, 3455 Adrenergic Receptor: Myszka DG, Rich RL, Tate CG, Identification of High Tehan B, Warne T, Congreve M. Affinity Arylpiperazine Leads Using Structure- Based Drug Design The Contrasting Activity of Antitumor Romero-Canelón I, Salassa L, 56(3), 1291– 38(6) Iodido versus Chlorido Sadler PJ. 1300 Ruthenium and Osmium Arene Azo- and Imino- pyridine Anticancer Complexes: Control of Cell Selectivity, Cross- Resistance, p53 Dependence, and Apoptosis Pathway The 2.5 Å Crystal Structure Not Zhao X, Allison D, Condon B, 56(3), 963–969 37(7) of the SIRT1 Catalytic specified Zhang F, Gheyi T, Zhang A, Ashok Domain Bound to S, Russell M, MacEwan I, Qian Y, Nicotinamide Adenine Jamison JA, Luz JG. Dinucleotide (NAD+) and an Indole (EX527 18

Analogue) Reveals a Novel Mechanism of Histone Deacetylase Inhibition Discovery of Epigenetic Antitumor Mirguet O, Gosmini R, Toum J, 56(19), 7501– 33(8) Regulator I-BET762: Lead Clément CA, Barnathan M, Brusq 7515 Optimization to Afford a JM, Mordaunt JE, Grimes RM, Clinical Candidate Inhibitor Crowe M, Pineau O, Ajakane M, of the BET Bromodomains Daugan A, Jeffrey P, Cutler L, Haynes AC, Smithers NN, Chung C, Bamborough P, Uings IJ, Lewis A, Witherington J, Parr N, Prinjha RK, Nicodème E. In Vitro and in Vivo Antitumor Palanimuthu D, Shinde SV, 56(3), 722–734 33(8) Anticancer Activity of Somasundaram K, Samuelson AG. Copper Bis(thiosemicarbazone) Complexes Membrane Localized Antitumor Cao R, Jia J, Ma X, Zhou M, Fei H. 56(9), 3636– 31(9) Iridium(III) Complex 3644 Induces Endoplasmic Reticulum Stress and Mitochondria-Mediated Apoptosis in Human Cancer Cells Structure-Based Design Antitumor Micco M, Collie GW, Dale AG, 56(7), 2959– 31(9) and Evaluation of Ohnmacht SA, Pazitna I, 2974 Naphthalene Diimide G- Gunaratnam M, Reszka AP, Neidle Quadruplex Ligands As S. Telomere Targeting Agents in Pancreatic Cancer Cells Discovery of a New Class of Antiparasiti Sharma S, Chauhan K, Shivahare R, 56(11), 4374– 30(10) Natural Product-Inspired c Vishwakarma P, Suthar MK, 4392 Quinazolinone Hybrid as Sharma A, Gupta S, Saxena JK, Lal Potent Antileishmanial J, Chandra P, Kumar B, Chauhan agents PMS. Fragment-Based Drug Antitumor Zhao L, Cao D, Chen T, Wang Y, 56(10), 3833- 30(10) Discovery of 2- Miao Z, Xu Y, Chen W, Wang X, Li 3851 Thiazolidinones as Y, Du Z, Xiong B, Li J, Xu C, Zhang Inhibitors of the Histone N, He J, Shen J. Reader BRD4 Bromodomain Optimization of 3,5- Antitumor Hewings DS, Fedorov O, 56(8), 3217- 30(10) Dimethylisoxazole Filippakopoulos P, Martin S, 3227 Derivatives as Potent Picaud S, Tumber A, Wells C, Bromodomain Ligands Olcina MM, Freeman K, Gill A, Ritchie AJ, Sheppard DW, Russell AJ, Hammond EM, Knapp S, Brennan PE, Conway SJ. Cloning, Characterization, Antiparasiti Pan P, Vermelho AB, Rodrigues 56(4), 1761- 30(10) and Sulfonamide and Thiol c GC, Scozzafava A, Tolvanen MEE, 1771 Inhibition Studies of an α- Parkkila S, Capasso C, Supuran CT. Carbonic Anhydrase from 19

Trypanosoma cruzi, the Causative Agent of Chagas Disease Sulfocoumarins (1,2- Antitumor Tars K, Vullo D, Kazaks A, Leitans J, 56(1), 293-300 30(10) Benzoxathiine-2,2- Lends A, Grandane A, Zalubovskis dioxides): A Class of Potent R, Scozzafava A, Supuran CT. and Isoform-Selective Inhibitors of Tumor- Associated Carbonic Anhydrases

2013: Perspectives Title Disease Authors Data Total area Cit. a (Rank) Principles and Applications Wilcken R, Zimmermann MO, 56(4), 1363– 134(1) of Halogen Bonding in Lange A, Joerger AC, Boeckler FM. 1388 Medicinal Chemistry and Chemical Biology Organosilicon Molecules Franz AK, Wilson SO. 56(2), 388–405 51(2) with Medicinal Applications Pharmacological Boyd RE, Lee G, Rybczynski P, 56(7), 2705– 46(3) Chaperones as Benjamin ER, Khanna R, Wustman 2725 Therapeutics for BA, Valenzano KJ. Lysosomal Storage Diseases Polypharmacology – Foe or Peters JU. 56(22), 8955– 39(4) Friend? 8971 Demystifying Brain Di L, Rong H, Feng B. 56(1), 2–12 39(4) Penetration in Central Nervous System Drug Discovery Sustainable Practices in Bryan MC, Dillon B, Hamann LG, 56(15), 6007- 32(5) Medicinal Chemistry: Hughes GJ, Kopach ME, Peterson 6021 Current State and Future EA, Pourashraf M, Raheem I, Directions Richardson P, Richter D, Sneddon HF

2014: Articles Title Disease Authors Data Total area Cit. a (Rank) Discovery of Ledipasvir Antiviral Link JO,Taylor JG, Xu L, Mitchell M, 57(5), 2033– 37(1) (GS-5885): A Potent, Once- (HCV) Guo H, Liu H, Kato D, Kirschberg T, 2046 Daily Oral NS5A Inhibitor Sun J, Squires N, Parrish J, Keller T, for the Treatment of Yang ZY, Yang C, Matles M, Wang Hepatitis C Virus Infection Y, Wang K, Cheng G, Tian Y, Mogalian E, Mondou E, Cornpropst M, Perry J, Desai MC. Discovery of AMG 232, a Antitumor Sun D, Li Z, Rew Y, Gribble M, 57(4), 1454– 27(2) Potent, Selective, and Bartberger MD, Beck HP, Canon J, 1472 20

Orally Bioavailable MDM2– Chen A, Chen X, Chow D, Deignan p53 Inhibitor in Clinical J, Duquette J, Eksterowicz J, Fisher Development B, Fox BM, Fu J, Gonzalez AZ, Gonzalez-Lopez De Turiso F, Houze JB, Huang X, Jiang M, Jin L, Kayser F, Liu JJ, Lo MC, Long AM, Lucas B, McGee LR, McIntosh J, Mihalic J, Oliner JD, Osgood T, Peterson ML, Roveto P, Saiki AY, Shaffer P, Toteva M, Wang Y, Wang YC, Wortman S, Yakowec P, Yan X, Ye Q, Yu D, Yu M, Zhao X, Zhou J, Zhu J, Olson SH, Medina JC. Ado-trastuzumab Antitumor Lambert JM, Chari RVJ. 57(16), 6949- 22(3) Emtansine (T-DM1): An 6964 Antibody–Drug Conjugate (ADC) for HER2-Positive Breast Cancer Discovery of ABT-267, a Antiviral DeGoey DA, Randolph JT, Liu D, 57(5), 2047– 22(3) Pan-Genotypic Inhibitor of (HCV) Pratt J, Hutchins C, Donner P, 2057 HCV NS5A Krueger PAC, Matulenko M, Patel S, Motter CE, Nelson L, Keddy R, Tufano M, Caspi DD, Krishnan P, Mistry N, Koev G, Reisch TJ, Mondal R, Pilot-Matias T, Gao Y, Beno DWA, Maring CJ, Molla A, Dumas E, Campbell A, Williams L, Collins C, Wagner R, Kati WM. Discovery of (10R)-7- Antitumor Johnson TW, Richardson PF, Bailey 57(11), 4720– 21(4) Amino-12-fluoro-2,10,16- S, Brooun A, Burke BJ, Collins MR, 4744 trimethyl-15-oxo- Cui JJ, Deal JG, Deng YL, Dinh D, 10,15,16,17-tetrahydro- Engstrom LD, He M, Hoffman J, 2H-8,4- Hoffman RL, Huang Q, Kania RS, (metheno)pyrazolo[4,3- Kath JC, Lam H, Lam JL, Le PT, h][2,5,11]- Lingardo L, Liu W, McTigue M, benzoxadiazacyclotetradec Palmer CL, Sach NW, Smeal T, ine-3-carbonitrile (PF- Smith GL, Stewart AE, Timofeevski 06463922), a Macrocyclic S, Zhu H, Zhu J, Zou HY, Edwards Inhibitor of Anaplastic MP. Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad- Spectrum Potency against ALK-Resistant Mutations Quinoline–Pyrimidine Antiparasiti Singh K, Kaur H, Smith P, de Kock 57(2), 435–448 21(4) Hybrids: Synthesis, c C, Chibale K, Balzarini J. Antiplasmodial Activity, SAR, and Mode of Action Studies Discovery of Danoprevir Antiviral Jiang Y, Andrews SW, Condroski 57(5), 1753– 20(5) 21

(ITMN-191/R7227), a (HCV) KR, Buckman B, Serebryany V, 1769 Highly Selective and Potent Wenglowsky S, Kennedy AL, Inhibitor of Hepatitis C Madduru MR, Wang B, Lyon M, Virus (HCV) NS3/4A Doherty GA, Woodard BT, Protease Lemieux C, Do MG, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD. Discovery of the First C- Antiviral Cho A, Zhang L, Xu J, Lee R, Butler 57(5), 1812– 19(6) Nucleoside HCV (HCV) T, Metobo S, Aktoudianakis V, Lew 1825 Polymerase Inhibitor (GS- W, Ye H, Clarke M, Doerffler E, 6620) with Demonstrated Byun D, Wang T, Babusis D, Carey Antiviral Response in HCV AC, German P, Sauer D, Zhong W, Infected Patients Rossi S, Fenaux M, McHutchison JG, Perry J, Feng J, Ray AS, Kim CU. Multitarget Drug Discovery Antimicoba Li K, Schurig-Briccio LA, Feng X, 57(7), 3126- 18(7) for Tuberculosis and Other cterial Upadhyay A, Pujari V, Lechartier 3139 Infectious Diseases B, Fontes FL, Yang H, Rao G, Zhu W, Gulati A, No JH, Cintra G, Bogue S, Liu YL, Molohon K, Orlean P, Mitchell DA, Freitas- Junior L, Ren F, Sun H, Jiang T, Li Y, Guo RT, Cole ST, Gennis RB, Crick DC, Oldfield E. Synthesis and Multitarget CNS Viayna E, Sola I, Bartolini M, De 57(6), 2549– 18(7) Biological Profiling of a Simone A, Tapia-Rojas C, Serrano 2567 Novel Family of Rhein FG, Sabaté R, Juárez-Jiménez J, Derivatives As Disease- Pérez B, Luque FJ, Andrisano V, Modifying Anti-Alzheimer Clos MV, Inestrosa NC, Muñoz- Agents Torrero D. Encoded Library Antimycob Encinas L, O’Keefe H, Neu M, 57(4), 1276– 18(7) Technology as a Source of acterial Remuiñán MJ, Patel AM, Guardia 1288 Hits for the Discovery and A, Davie CP, Pérez-Macías N, Yang Lead Optimization of a H, Convery MA, Messer JA, Pérez- Potent and Selective Class Herrán E, Centrella PA, Álvarez- of Bactericidal Direct Gómez D, Clark MA, Huss S, Inhibitors of O’Donovan GK, Ortega-Muro F, Mycobacterium McDowell W, Castañeda P, Arico- tuberculosis InhA Muendel CC, Pajk S, Rullás J, Angulo-Barturen I, Álvarez-Ruíz E, Mendoza-Losana A, Pages LB, Castro-Pichel J, Evindar G. Discovery of Highly Potent, Antitumor Estrada AA, Chan BK, Baker-Glenn 921–936 17(8) Selective, and Brain- C, Beresford A, Burdick DJ, Penetrant Aminopyrazole Chambers M, Chen H, Dominguez Leucine-Rich Repeat SL, Dotson J, Drummond J, Flagella Kinase 2 (LRRK2) Small M, Fuji R, Gill A, Halladay J, Harris Molecule Inhibitors SF, Heffron TP, Kleinheinz T, Lee DW, Le Pichon CE, Liu X, Lyssikatos JP, Medhurst AD, Moffat JG, Nash K, Scearce-Levie K, Sheng Z, Shore DG, Wong S, Zhang S, Zhang X, 22

Zhu H, Sweeney ZK. Cyclic Secondary Antitumor Moeker J, Peat TS, Bornaghi LF, 57(8), 3522– 16(9) Sulfonamides: Unusually Vullo D, Supuran CT, Poulsen SA. 3531 Good Inhibitors of Cancer- Related Carbonic Anhydrase Enzymes Pan-Histone Demethylase Antitumor Rotili D, Tomassi S, Conte M, 57(1), 42–55 16(9) Inhibitors Simultaneously Benedetti R, Tortorici M, Ciossani Targeting Jumonji C and G, Valente S, Marrocco B, Labella Lysine-Specific D, Novellino E, Mattevi A, Altucci Demethylases Display High L, Tumber A, Yapp C, King ONF, Anticancer Activities Hopkinson RJ, Kawamura A, Schofield CJ, Mai A. The Discovery of I-BET726 Antitumor Gosmini R, Nguyen VL, Toum J, 57(19), 8111– 15(10) (GSK1324726A), a Potent Simon C, Brusq JMG, Krysa G, 8131 Tetrahydroquinoline Mirguet O, Riou-Eymard AM, ApoA1 Up-Regulator and Boursier EV, Trottet L, Selective BET Bamborough P, Clark H, Chung C, Bromodomain Inhibitor Cutler L, Demont EH, Kaur R, Lewis AJ, Schilling MB, Soden PE, Taylor S, Walker AL, Walker MD, Prinjha RK, Nicodème E. A Low Cytotoxic Cationic Delivery Hu Q, Yu J, Liu M, Liu A, Dou Z, 57(13), 5679– 15(10) Metal–Organic Framework Yang Y. 5685 Carrier for Controllable Drug Release Discovery of a Highly Antitumor Clavel CM,Păunescu E, Nowak- 57(8), 3546– 15(10) Tumor-Selective Sliwinska P, Griffioen AW, 3558 Organometallic Scopelliti R, Dyson PJ. Ruthenium(II)–Arene Complex Hepatitis C Virus NS5A Antiviral Belema M, Nguyen VN, Bachand 57(5), 2013– 15(10) Replication Complex (HCV) C, Deon DH, Goodrich JT, James 2032 Inhibitors: The Discovery CA, Lavoie R, Lopez OD, Martel A, of Daclatasvir Romine JL, Ruediger EH, Snyder LB, St. Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O’Boyle II DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG. Synthesis, Cytostatic, Antiviral Nauš P, Caletková O, Konečný P, 57(2), 1097– 15(10) Antimicrobial, and Anti- (HCV), Džubák P, Bogdanová K, Kolář M, 1110 HCV Activity of 6- antitumor, Vrbková J, Slavětínská L, Substituted 7-(Het)aryl-7- antimicrobi Tloušt’ová E, Perlíková P, Hajdúch deazapurine al M, Hocek M. Ribonucleosides [1,2,4]Triazolo[4,3- Not Fedorov O, Lingard H, Wells C, 57(2), 462–476 15(10) a]phthalazines: Inhibitors specified Monteiro OP, Picaud S, Keates T, of Diverse Bromodomains Yapp C, Philpott M, Martin SJ, Felletar I, Marsden BD, 23

Filippakopoulos P, Müller S, Knapp S, Brennan PE.

2014: Perspectives Title Disease Authors Data Total area Cit. a (Rank) Data-Mining for Sulfur and Ilardi EA, Vitaku E, Njardarson JT. 57(7), 2832– 49(1) Fluorine: An Evaluation of 2842 Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery Macrocyclic Drugs and Giordanetto F, Kihlberg J. 57(2), 278–295 45(2) Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties? Hydrocarbon-Stapled Walensky LD, Bird GH. 57(15), 6275– 44(3) Peptides: Principles, 6288 Practice, and Progress Rings in Drugs Taylor RD, MacCoss M, Lawson 57(14), 5845– 40(4) ADG. 5859 Analysis of the Structural Vitaku E, Smith DT, Njardarson JT. 57(24), 10257– 36(5) Diversity, Substitution 10274 Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals QSAR Modeling: Where Cherkasov A, Muratov EN, 57(12), 4977- 36(5) Have You Been? Where Fourches D, Varnek A, Baskin II, 5010 Are You Going To? Cronin M, Dearden J, Gramatica P, Martin YC, Todeschini R, Consonni V, Kuz’min VE, Cramer R, Benigni R, Yang C, Rathman J, Terfloth L, Gasteiger J, Richard A, Tropsha A.

Table S1. 10-Top cited Ms and 5-top cited perspectives appeared in J. Med. Chem. during 2005- 2014. Analysis was performed October 13th, 2015. a: some Ms possess the same number of citations; these Ms have been reported as possessing the same ranking.

Hits (Graph S1A) 70 60 50 40 Hit Public 30 Hit Private 20 Hit Public+ 10 Hit Private+ % Msdealingwithdrugdisc. 0 2005 2006 2008 2010 2012 2014 Years

Clinical candidates (Graph S1B) 9 8 7 6 5 Public 4 Private 3 Public+ 2 1 Private+ % Msdealingwithdrugdisc. 0 2005 2006 2008 2010 2012 2014 Years

Graphs S1 A,B. Percentage (%) of Ms on J. Med. Chem. dealing with hits and clinical candidates discovery with respect to the total number of Ms dealing with drug discovery. Graph about leads is reported in the main text (Graph 8). These data have been obtained for the years 2005, 2006, 2008, 2010, 2012 and 2014. Public: public sector, Private: private sector, Public+: partnerships by authors from the public and private sectors, with the corresponding author from the public sector; Private+: partnerships by authors from the public and private sectors, with the corresponding author from the private sector.

2005 Number of Ms Total 857 Ms (598 drug disc.)a Category Hit Leads Clinical candidates Public 336 6 1 Private 78 54 27 Public+ 57 1 0 Private+ 24 9 5 2006 Number of Ms Total 845 Ms (601 drug disc.) a Category Hit Leads Clinical candidates public 386 1 0 private 61 53 27 Public+ 52 2 0 Private+ 12 2 5 2008 Number of Ms Total 839 Ms (577 drug disc.) a Category Hit Leads Clinical candidates public 355 6 0 private 41 75 30 Public+ 37 5 1 Private+ 17 7 3 2010 Number of Ms Total 729 Ms (569 drug disc.) a Category Hit Leads Clinical candidates Public 337 19 1 Private 36 60 39 Public+ 45 4 0 Private+ 13 11 4 2012 Number of Ms Total 834 Ms (660 drug disc.) a Category Hit Leads Clinical candidates Public 363 48 0 Private 22 92 40 Public+ 53 8 1 Private+ 12 14 7 2014 Number of Ms Total 680 Ms (558 drug disc.) a Category Hit Leads Clinical candidates Public 318 47 1 Private 17 77 43 Public+ 24 10 0 Private+ 8 9 4

Table S2. Analysis of J. Med. Chem. Ms content. a: the brackets report the number of Ms dealing with hits (a molecule with known structure and a robust dose-response activity in a primary screen, or representative of a series with activity via an acceptable mechanism of action and some preliminary structure-activity relationships), lead (a representative of a series with sufficient potential, measured by potency, selectivity, pharmacokinetics, physicochemical properties, to progress to a full development program) or a clinical candidate. 26

60 50 40 30 20

Number ofMs 10 0

Graph S2. Number of Ms dealing with New Molecular Entities (NMEs) that received first time approval worldwide during the period 2005-2013, described for the first time in J. Med. Chem., in comparison with the other journals reported in Graph 1. A search on Scifinder of the 230 NMEs approved during years from 2005 to 2013 (2014 is not yet available) reported in the “Annual Reports in Medicinal Chemistry” [S1-S9] yielded Table S3 and Graph S2. We decided to show only a cumulative result, and not a classification for each year, since publication date can vary greatly with respect to the approval date: for example, ivacaftor, approved in 2012, was described for the first time in 2014 [S10] while pixantrone dimaleate, approved in 2012 as well, has been described in J. Med. Chem. in 1994 [S11]. Articles containing only activity without compound description (analytical and spectroscopic data) have not been considered as “first time publication”; for example, ivacaftor activity was reported in 2009 [S12], but it was not considered in the present analysis. It should be noted that ACS Med Chem. Lett. started to be published only in 2010 and ChemMedChem in 2007. The other journals reported in Graph 1 (Eur. J. Med. Chem., J. Enzyme Inh. Med. Chem. and Med. Chem.), to the best of our knowledge, do not contain articles describing for the first time approved NMEs during 2005-2013.

New Molecular Entity Year of first launch Bibliographic data (NMEs) 2013 (27 NMEs) [S1] Canagliflozin J. Med. Chem. 2010, 53, 6355. Cobicistat ACS Med. Chem. Lett. 2010, 1, 209. Dabrafenib ACS Med. Chem. Lett. 2013, 4, 358. Dolutegravir J. Med. Chem. 2013, 56, 5901. Elvitegravir J. Med. Chem. 2006, 49, 1506. Ibrutinib ChemMedChem 2007, 2,58. Istradefylline Bioorg. Med. Chem. Lett. 1997, 18, 2349. Macitentan J. Med. Chem. 2012, 55, 7849. Olodaterol Bioorg. Med. Chem. Lett. 2010, 20, 1410. Pomalidomide Bioorg. Med. Chem. Lett. 1999, 9, 1625. Riociguat ChemMedChem 2009, 4, 853. Simeprevir Bioorg. Med. Chem. Lett. 2008, 18, 4853. Sofosbuvir J. Med. Chem. 2010, 53, 7202. Trametrinib ACS Med. Chem. Lett. 2011, 2, 320 Vortioxetine J. Med. Chem. 2011, 54, 3206. 2012 (30 NMEs) [S2] Aclidinium bromide J. Med. Chem. 2009, 52, 5076. Anagliptin Bioorg. Med. Chem. 2011, 19, 7221. Bosutinib J. Med. Chem. 2001, 44, 3965. Dapagliflozin J. Med. Chem. 2008, 51, 1145. Enzalutamide J. Med. Chem. 2010, 53, 2779. Ivacaftor J. Med. Chem. 2014, 57, 9776. Lorcaserin hydrochloride J. Med. Chem. 2008, 51, 305. Pasireotide J. Med. Chem. 2003, 46, 2334. Perampanel J. Med. Chem. 2012, 55, 10584. Pixantrone dimaleate J. Med. Chem. 1994, 37, 828. Ponatinib J. Med. Chem. 2010, 53, 4701. Teneligliptin Bioorg. Med. Chem. 2012, 20, 5705. Vismodegib Bioorg. Med. Chem. Lett. 2009, 19, 5576. 2011 (26 NMEs) [S3] Abiraterone acetate J. Med. Chem. 1995, 38, 2463. Apixaban J. Med. Chem. 2007, 50, 5339. Boceprevir J. Med. Chem. 2006, 49, 6074. Crizotinib J. Med. Chem. 2011, 54, 6342. Linagliptin J. Med. Chem. 2007, 50, 6450. Rilpivirine J. Med. Chem. 2005, 48, 1901. Vandetanib J. Med. Chem. 2002, 45, 1300. Vilazodone hydrochloride J. Med. Chem. 2004, 47, 4684. 2010 (24 NMEs) [S4] Alogliptin J. Med. Chem. 2007, 50, 2297. Ceftaroline fosamil Bioorg. Med. Chem. 2003, 11, 2427. Diquafosol Bioorg. Med. Chem. Lett. 2001, 11, 157 Eribulin mesylate Bioorg. Med. Chem. Lett. 2004, 14, 5551. Fingolimod hydrochloride J. Med. Chem. 2000, 43, 2946. Laninamivir octanoate Bioorg. Med. Chem. Lett. 2009, 19, 2938. Peramivir J. Med. Chem. 2000, 43, 3482. Ticagrelor Bioorg. Med. Chem. Lett. 2007, 17, 6013.

Zucapsaicin J. Med. Chem. 1993, 36, 2595. 2009 (28 NMEs) [S5] Degarelix acetate J. Med. Chem. 2001, 44, 453. Eslicarbazepine acetate J. Med. Chem. 1999, 42, 2582. Indacaterol J. Med. Chem. 2010, 53, 3675. Liraglutide J. Med. Chem. 2000, 43, 1664. Pazopanib J. Med. Chem. 2008, 51, 4632. Pralatrexate J. Med. Chem. 1993, 36, 2228. Saxagliptin J. Med. Chem. 2005, 48, 5025. Tolvaptan Bioorg. Med. Chem. 1999, 7, 1743. 2008 (24 NMEs) [S6] Alvimopan J. Med. Chem. 1994, 37, 2262. Dabigatran etexilate J. Med. Chem. 2002, 45, 1757 Desvenlafaxine J. Med. Chem. 1990, 33, 2899. Etravirine Bioorg. Med. Chem. Lett. 2001, 11, 2235. Fosaprepitant J. Med. Chem. 2000, 43, 1234. Dimeglumine Lacosamide J. Med. Chem. 1996, 39, 1907. Rrivaroxaban J. Med. Chem. 2005, 48, 5900. Sitafloxacin J. Med. Chem. 1994, 37, 3344. 2007 (20 NMEs) [S7] Ambrisentan J. Med. Chem. 1999, 42, 3026. Imidafenacin Bioorg. Med. Chem. Lett. 1998, 8, 1807. Lapatinib Bioorg. Med. Chem. Lett. 2006, 16, 4686. Raltegravir J. Med. Chem. 2008, 51, 5843 Vildagliptin J. Med. Chem. 2003, 46, 2774 2006 (27 NMEs) [S8] Anidulafungin J. Med. Chem. 1995, 38, 3271. Darunavir J. Med. Chem. 2005, 48, 1813. Dasatinib J. Med. Chem. 2006, 49, 6819. Mozavaptan J. Med. Chem. 1996, 39, 3547. Sitagliptin J. Med. Chem. 2005, 48, 141. Sitaxentan J. Med. Chem. 1997, 40, 1690. Sunitinib J. Med. Chem. 2003, 46, 1116. Varenicline J. Med. Chem. 2005, 48, 3474. Vorinostat J. Med. Chem. 1995, 38, 1411. 2005 (24 NMEs) [S9] Entecavir Bioorg. Med. Chem. Lett. 1997, 7,127. Nepafenac J. Med. Chem. 1990, 33, 2296 Ramelteon J. Med. Chem. 2002, 45, 4222 Tigecycline Bioorg. Med. Chem. Lett. 1999, 9, 1459. Tipranavir J. Med. Chem. 1996, 39, 4349

Table S3: Ms dealing with New Molecular Entities (NMEs) that received first time approval worldwide during the period 2005-2013, described for the first time in J. Med. Chem. and the other journals reported in Graph 1. These data have been used for the drawing of Graph S2.

Supplementary references

[S1] Bronson, J.; Black, A.; Dhar, T.G.M.; Ellsworth, B.A.; Merritt, J.R. To market, to market- 2013. Ann. Rep. Med. Chem. 2014, 49, 437-508.

[S2] Bronson, J.; Black, A.; Dhar, T.G.M.; Ellsworth, B.A.; Merritt, J.R. To market, to market- 2012. Ann. Rep. Med. Chem. 2013, 48, 471-546.

[S3] Bronson, J.; Dhar, M.; Ewing, W.; Lonberg, N. To market, to market-2011. Ann. Rep. Med. Chem. 2012, 47, 499-569.

[S4] Bronson, J.; Dhar, M.; Ewing, W.; Lonberg, N. To market, to market-2010. Ann. Rep. Med. Chem. 2011, 46, 433-502.

[S5] Hegde, S.; Schmidt, M. To market, to market-2009. Ann. Rep. Med. Chem. 2010, 45, 467-537.

[S6] Hegde, S.; Schmidt, M. To market, to market-2008. Ann. Rep. Med. Chem. 2009, 44, 577-632.

[S7] Hegde, S.; Schmidt, M. To market, to market-2007. Ann. Rep. Med. Chem. 2008, 43, 455-497.

[S8] Hegde, S.; Schmidt, M. To market, to market-2006. Ann. Rep. Med. Chem. 2007, 42, 505-554.

[S9] Hegde, S.; Schmidt, M. To market, to market-2005. Ann. Rep. Med. Chem. 2006, 41, 439-477.

[S10] Hadida, S.; Van Goor, F.; Zhou, J.; Arumugam, V.; McCartney, J.; Hazlewood, A.; Decker, C.; Negulescu, P.; Grootenhuis, P.D.J. Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo- 1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a potent and orally bioavailable CFTR potentiator. J. Med. Chem. 2014, 57, 9776-9795.

[S11] Krapcho, A.P.; Petry, M.E.; Getahun, Z.; Landi, J.J.; Stallman, J.; Polsenberg, J.F.; Gallagher, C.E.; Maresch, M.J.; Hacker, M.P. 6,9-bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: synthesis and antitumor evaluation. J. Med. Chem. 1994, 37, 828-837.

[S12] Van Goor, F.; Hadida, S.; Grootenhuis, P.D.J.; Burton, B.; Cao, D.; Neuberger, T.; Turnbull, A.; Singh, A.; Joubran, J.; Hazlewood, A.; Zhou, J.; McCartney, J.; Arumugam, V.; Decker, C.; Yang, J.; Young, C.; Olson, E.R.; Wine, J.J.; Frizzell, R.A.; Ashlock M.; Negulescu, P. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc. Natl. Acad. Sci. USA 2009, 106, 18825-18830.