Medicinal Chemistry and Chemical Biology Chimia 2013, 67, Nr
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medicinal chemistry and chemical biology Chimia 2013, 67, Nr. 7/8 519 doi:10.2533/chimia.2013.519 Chimia 67 (2013) 519–543 © Schweizerische Chemische Gesellschaft MedicinalChemistry Chemical Biology MC001 Medicinal ChemistryChemical Bioloy MC002 SOM230:Anew therapeuticmodality for Cushing’s disease Directed evolution of bicyclic peptides fortherapeutic application Ian Lewis, Janos Pless, Rainer Kneuer, Antonio P. Silva, Daniel Hoyer, Gisbert Lisa Pollaro, Alessandro Angelini, KhanMaola andChristian Heinis Weckbecker, ChristianBruns and Herbert A. Schmid EPFL, BCH5305, 1015 Lausanne,Switzerland GlobalDiscovery Chemistry Department ExploratoryMedicinal Chemistry Unit andAutoimmune, Oncologyand Neuroscience Research Departments, Bicyclic peptideswith highbinding affinity andtargetselectivitycan be NovartisInstitutesofBiomedicalResearch, CH-4002 Basel,Switzerland isolated from large combinatoriallibrariesbyphage display as shown in the figurebelow. In brief,peptide librariesdisplayed on phage arecyclizedina The somatostatin (SRIF,somatotropinrelease inhibiting factor) field has chemical reactionand subjected to affinity selections. The bicyclic peptides been asuccess story in termsofmedicinal chemistryand drug discovery combine keyqualities of antibodytherapeutics (high affinity andspecificity) offering avariety of therapeutic opportunities, e.g. acromegaly, gastrointes- andsomeadvantagesofsmall molecule drugs. tinal neuroendocrine tumors, whole body imaging and radiotherapy. Indeed, arational medicinal chemistry approach capitalising on structure activity relationships led to the discovery of SOM230, astable cyclohexapeptide somatostatinmimic which exhibits unique bindingtohuman SRIF receptors (sst1-5). This approach involved transposing functionalgroups, in the form of unnatural amino acids, from SRIF-14 intothe stable,reduced size cyclo- hexapeptide template. Further, the hydroxyproline urethane extension of SOM230 has been functionalized with the chelators DTPA and DOTA, which is anecessary prerequisite forthe possibledevelopment of ligands which couldbeused for whole body imaging. Uniquely, SOM230exhibits binding with a30to40times higher affinity than Sandostatin® to the sst1 and sst5 receptors and exhibits higher efficacy in preclinical models in low- ering Growth Hormone, Insulin-Like Growth Factor-1, ACTH and corti- Potent andselective bicyclic peptide inhibitorsofthe cancer-associated costeronethanSandostatin®.Recently, phase III clinical studies have estab- proteasesurokinase-type plasminogenactivator (uPA) andmatrix lished thetherapeutic potential of SOM230 /Pasireotide (Signifor®), as the metalloproteinase 2(MMP-2) were recentlydeveloped. The properties of 1 first pituitary directedmedical therapyfor Cushing’s disease leadingto these inhibitorsand their structureswill be discussedaswellasfirst in vivo registration of SOM230 by both EMEA and FDA in 2012. resultspresented. [1] Annamaria Colao, Stephan Petersenn, JohnNewell-Price,James W. [1]Heinis, C., et al., Nat. Chem.Biol.. 2009, 5,502. Findling,FengGu, MarioMaldonado,UlrikeSchoenherr, DavidMills, [2]Angelini, A., et al., ACS Chem.Biol. 2012, 18,817 Luiz RobertoSalgado and Beverly M.K. Biller for the PasireotideB2305 [3]Angelini, A., et al., J. Med. Chem., 2012, 26,10187 StudyGroup,A12-MonthPhase 3Study of Pasireotide in Cushing’s Dis- ease, NEngl JMed 2012;366:914-24. MedicinalChemistryChemical Biology MC003 Medicinal Chemistry Chemical Biology MC004 Non-nucleosidicCOMTbisubstrate inhibitors Synthesisand testing of photoaffinity probes forthe site-selective chemical modificationsofthe 5-HT3 receptor Christian Lerner,[a] Caterina Bissantz,[a] BerndBüttelmann,[a] François Diederich,[b] AlainGast,[a] Roland Jakob-Roetne,[a] Thomas Jack*, Marc-DavidRuepp*,Oliver Mhlemann*, Andrew J. DorisRoth, [a] Markus Rudolph,[a] Daniel Schlatter[a] Thomsonǂ,Sarah C. R. Lummisǂ andMartinLochner* [a]F.Hoffmann-La RocheLtd., 4070 Basel, Switzerland *University of Bern,DCB,Freiestrasse 3, CH-3012Bern [b]ETH Zurich,8093 Zurich,Switzerland ǂUniversity of Cambridge, TennisCourt Road,CB2 1QWCambridge, UK Inhibitionofcatechol O-methyltransferase(COMT)inthe brainisexpected The5-HT3 receptor (5-HT3R) isanimportant ion channel responsiblefor to be an effectivetreatment of depression andinparticular of disturbedcog- thetransmission of nerve impulses inthecentral nervoussystem.1 It isdiffi- nitiveperformanceinschizophrenia.Tolcapone(1)with averylow culttocharacterizetransmembranedynamicreceptors with classical struc- brain/plasma ratio of ~0.01 hasbeenusedasatool compound to studythe tural biology approaches likecrystallization and x-ray.Theuse of central effectsofCOMTinhibitioninclinical trials andinanimalexperi- photoaffinity probes isanalternativeapproach to identify regions inthe ments[1].Research in collaborationwith theDiederich group at theETH proteinthat are importantfor thebinding of small molecules.Therefore we Zurich ledtothe discoveryofpotentnucleosidicbisubstrateinhibitors (2) synthesized asmall library of photoaffinity probes by conugating that bind to both, thecatechol substratepocketand S-adenosylmethionine photophores via various linkers to granisetron whichisaknownantagonist (SAM)cofactorpocketofCOMT[2].Inthispresentation, we shownon- of the5-HT3R. We were abletoobtainseveral compounds with diverse nucleosidicbisubstrateinhibitors (3)thatwere discovered using parallel linker lengthsand differentphotolabile moieties that show nanomolar bind- chemistrybased on virtualdocking andchemical intuition. ing affinities fortheorthostericbinding site.Furthermore weestablished a stable h5-HT3Rexpressing cell line andapurification protocol to yieldthe O receptor inahigh purity.Currently weare investigating thephotocrosslink- O N R1 2 NH O 2 ing of these ligands with the5-HT3R. NO 2 N N linker R2 N HO OH HO OH H N HO OH O N 1 2 3 HO OH Tolcapone nucleosidicbisubstrate inhibitor non-nucleosidicbisubstrate inhibitors [1]J.A.Apud, D. R. Weinberger, CNS Drugs 2007, 21,535. [2]C.Lerner,A.Ruf,V.Gramlich, B. Masjost, G. Zürcher, R. Jakob- Roetne,E.Borroni,F.Diederich, Angew.Chem. 2001, 113,4164; Angew. [1]Thompson, A. J.;Lummis, S. C., Expert Opin.Ther. Targets 2007, 11, Chem.-Int. Edit. 2001, 40,4040. 527. 520 Chimia 2013, 67, Nr. 7/8 medicinal chemistry and chemical biology MedicinalChemistry Chemical Biology MC005 Medicinal ChemistryChemicalBiology MC006 DiscoveryofHighly Potent S1P1 Receptor Antagonists With In Vivo Structural Insights into E-selectin-Ligand Interactions Efficacy Roland C. Preston1,Florian P.C. Binder1,Mirco Zierke1,Roman Jakob2, Jean Quancard, Birgit Bollbuck, Daniela Angst, Philipp Janser, Frédéric Timm Maier2,Beat Ernst1 Berst, Peter Buehlmayer, Markus Streiff, Christian Beerli, Volker Brink- mann, Danilo Guerini, Paul A. Smith, TimSeabrook, Martin Traebert, 1Institute of Molecular Pharmacy, Pharmazentrum, University of Basel, KlausSeuwen, René Hersperger,ChristianBruns,Frédéric Bassilana,Marc Klingelbergstr. 50/70, CH-4056 Basel Bigaud 2Biozentrum, University of Basel, Klingelbergstr. 50/70, CH-4056 Basel NovartisInstitutesfor BioMedicalResearch, Basel, Switzerland The lectin E-selectin is involved in avariety of inflammatory diseases by acting as leukocyte-adhesive protein on the cardiovascular endothelium. E- We presentthe identification of anovel S1P1 receptor antagonist scaffold by selectin has extensively been under investigation as drug target. HTS, followed by asuccessful optimization to afford single digit nanomolar We investigated the binding of sialyl Lewisx (1,sLex)and the affinity- tool compounds for subcutaneous administration. First in vivo studiesinrats improved glycomimetic 2 by X-ray crystallography. Co-crystallization of demonstratedimmunomodulatory properties, kicking-off abroad strategy to ligand and protein revealed significant conformational alterations of the addressthe scaffold inherent bioavailability issues. These efforts ultimately binding site upon binding, when compared to published apo- and sLex (1) led to the discovery of NIBR-0213. Oral administration of this highly potent soaked structures [1, 2]. In the induced conformation, additional hydrogen andselective S1P1 receptor antagonist induceslong lasting reductionofpe- bonds between the protein and the ligand are observed. We further investi- ripheral blood lymphocyte counts leading to efficacy in relevant animal gated the binding of antagonist 3 with afivefold improved affinity over 2. models of autoimmune diseases. The structural data reveals asigma-pi interaction of the benzoate moiety in the 2-position of the D-Gal moiety with the (S)-cyclohexyl lactic acid, lead- ing to an improved preorganizationofthe carboxylic acid in its bioactive conformation. In addition, aminor shift of the (S)-cyclohexyl lactic acid moity was observed, allowing for closer contact of this moiety in antagonist 3 to the protein. These insights provide the basis for future rational in silico design of potent E-selectin antagonists. Flexibility 1,sLex 2 3 HO AcHN OH KD=878 µM KD=19µM KD =4µM Rigidity HO HO O OH H H OH OH O O O O O O O OSE O O O O O O O O O O O NHAc O HO O OH Me O Me OH HO O HO O OH OH OH OH OH Protein Surface OH OH OH HO HO HO [1] Graves, B.J. et al. Nature, 1994, 367,532-538. [2] Somers, W.S. et al. Cell, 2000,103,467-479. Medicinal Chemistry Chemical Biology MC007 MedicinalChemistryChemical Biology MC008 Imidazolinesand Imidazoles as TAAR1Agonists Functionalized nanomaterials forcancer diagnosis Guido Galley,AnnickGoergler,Marius C. Hoener, RogerD.Norcross and SolènePassemard1,DavideStaedler1,Giona