(ADME) 35, 36, 62, 72, 264 Academics Acyclic Nucleoside Phosphona

291

Index a activated prothrombin complex Abraxane 17 concentrate (aPCC) 224, absorption, distribution, 239–240, 242 metabolism and excretion active pharmaceutical ingredients (ADME) 35, 36, 62, 72, 264 (API) 117 academics acyclic nucleoside phosphonates acyclic nucleoside phosphonates 29–31 29–31 adoptive cell transfer 160–161 anti-cancer drugs 12–20 alanine scanning 91–92 antibiotics 11 albiglutide 100 artemisinin and artemether and albenatide 100 20–21 alglucerase 26–27 biologic drugs 23–27 amino acid replacements 234 carfilzomib 21–23 4-aminobutyrate-oxo-glutarate darunavir 31–32 aminotransferase 8 histonedeacetylase inhibitors angiogenesis 6, 199 27–29 annualized bleeding rates (ABRs) monoclonal anti-CD20 antibody 236–237, 239–241 5 α-anomer 130 patent lifetime 4 anti-cancer drugs pregabalin 8–10 camptothecin 12–14 rituximab 5 epothilones 17–18 sunitinib 32–33 eribulin 18–20 thalidomide derivatives 5, 6 Taxol 14–17 activated partial thromboplastin anti-drug (emicizumab) antibodies time (APTT) 226–227, 230, (ADAs) 236, 241–242 235–236 antibiotics 11–12, 34 activated Protein C (aPC)-catalyzed antigen presenting cells (APCs) FVa inactivation 225 162–165

antihyperglycemic agents 111, alpha-CGRP 199 136–137 beta-CGRP 199 antihyperglycemic drugs 111, 113, gut, role of 203 115 indications 211–212 aromatic amine analogs 254 migraine treatment artemether 20–21 allodynia 204 artemisinin 20–21 central and peripheral nervous aryl C-glucoside 114, 125 systems 203 7-azabenzimidazole 277 clinical correlation 203 azeotropic distillation 117 inflammatory cascade 203 large molecule antagonists b 208–211 benzimidazole 277 neuronal plasticity and synapse o-Cl benzaldehyde 261 formation 204 p-benzophenone 116 polymodal nociceptors o-benzylphenol aglycones 204–208 114–115 small molecule antagonists bexagliflozin 114, 122–123, 204 136–137, 140, 142 systemic circulation and levels biologic drugs 200 alglucerase 26–27 trigeminal nucleus caudalis insulin 23–25 (TNC) 203 rituximab 25–26 neuropeptide 199 biomarkers 172–173, 226, 235 physiological role 200–202 boron trifluoride etherate small molecule CGRP-RA 207 116–117, 119, 121, 122, 125, camptothecin 12–14 127–128, 131 canagliflozin 111, 125, 129–133, bortezomib 22, 23, 48 137–139, 141–143 breast cancer 18, 20, 160, 273–285 Cannizzaro reaction 129 5-bromo-2-chloro analog 120 capsaicin 200, 203 5-bromo-2-chlorobenzoic acid 115 CAR T cells 4-bromo-1-chloro-2-[(4-ethoxy- antigen recognition and response phenyl)methyl]benzene 117 166 2-bromoisonicotinonitrile 261 approved therapies 186–187 N-bromosuccinimide 128 biomarkers of 172–173 cancer therapy 179 c clinical trials 181–182 C-terminus biphenyl alanine 102 cytokine release syndrome calcitonin gene-related peptide 173–174 (CGRP) 209 FDA approval 169 Index 293

first generation CARs 167 cutaneous T-cell lymphoma (CTCL) human clinical trial 161–162 29 licensing strategy 184 cyclin-dependent kinases (CDKs) long-lasting memory response 273–274, 276, 278–279 167–168 cyclosporine 64 neurotoxicity 174–175 cytokine release syndrome 161, “on-target, off-tumor” toxicity 173–174 175–176 cytosolic 50 pharmacokinetic profiles expansion 170–171 d persistence 171–172 dapagliflozin 111, 114–117, 121, trafficking 172 125, 129, 136–144 pre-registration therapies darunavir 31–32 187–188 De Clercq, Erik 29–30, 35 production issues 176–179 DECLARE-TIMI 58 trial 137, quality assurance (QA) unit 184 140–142 quality control release testing Degraders 47–71, 284 183 polar surface area (PSA) and retrospective analysis 185 partition coefficient 50 therapeutic application 167, 169 dienone-yne substrate 127 therapeutic resistance 179–182 3,3-difluorocyclobutan-1-amine carbon-linked heterocycles 254 hydrochloride 260–261 carfilzomib 21–23, 48 dihydroisobenzofuran moiety 127 CART19 cells 170–175, 180, 184, dimethylamide 278, 280 188 4,4-dimethyltetrahydrofuran ring CDK4/6 inhibitors 273–285 121 CeredaseTM 27 dipeptidyl peptidase-IV (DPP-IV) chemotherapy 6–8, 12–13, 16, 187 90–91, 141 chimeric antigen receptor (CAR) 2,N-diphenyl glycine inhibitor 251 166, 175–176, 180, 183 2,N-diphenyl glycine scaffold design and evolution 168 251–252 coagulation system 236 DNA hypermethylation 249 combination treatments 282–283, DPP-4 inhibitors 141–142 285 drug discovery 3–36, 54, 58, 66–71, complementarity-determining 89, 156, 170, 224–225, 285 region (CDR) 161, 163, 234 from academic groups 3 computer assisted methods 3 drug metabolism and CREDENCE trial 139 pharmacokinetics (DMPK) cross-coupling reaction 131 optimization strategy 62, cryo electron microscopy (EM) 91 256, 267 294 Index

druggable proteome 58–59 single ascending dose studies dulaglutide 93, 95, 98–99 235–236 recombinantFVIIa (rFVIIa) e product 224 efpeglenatide 94–95 empagliflozin 111, 113, 119–125, emicizumab (HEMLIBRA) 138–143 activatedprothrombin complex endogenous T cell receptors (TCRs) concentrate (aPCC) 224 161–166, 169 anti-FVIII neutralizing enzymatic assay system 230 alloantibodies 224 enzyme-linked immunosorbent application of technology 233 assay (ELISA) 279 asymmetric bispecific IgG epothilones 17–18 antibody 225–226 epoxomicin 21–23 bleeding prophylactic treatment eptinezumab 208–210 223 equilibrium dialysis method 256 clinical pharmacology erenumab 202, 208, 210 investigations eribulin 18–20 bioavailability study 238–239 erythema nodosum leprosum 50 model-informed phase III dose p-ethylbenzoyl chloride 127 selection 237–238 4-ethylphenyl magnesium bromide common light chain, of 127 asymmetric bispecific IgG eukaryotic cell cycle 274 antibody 232 extended half-life (EHL) FVIII event-driven pharmacology products 224 61–62, 66 gene encoding FVIII 223 Ex4 based analogues homodimerized antibodies 233 efpeglenatide 94–95 identification of clinical candidate exenatide 92–94 226–229 exenatide long-acting release in vivo characteristics of (LAR) 94 230–231 lixisenatide 94 late-phase clinical development pegylatedloxenatide 95 non-interventional study 239 exenatide 92–95 phase III studies 239–242 exenatide long-acting release (LAR) mechanism of action and in vitro 94 characteristics 229–230 exendin-4 90 phase I and I/II studies extracellular domain (ECD) multiple ascending dose studies 91–92, 102, 163 236 extracellular scFV 166 Index 295 f semaglutide 96–97 Fab sequences 227 taspoglutide 97–98 fluorescence-activated cell sorting incretins 89 (FACS) analysis 281 peptide sequence 90, 163 2-(4-fluorophenyl)-5-(5-iodo-2- T2DM and obesity treatment methylbenzyl)thiophene dipeptidyl peptidase-IV 132 (DPP-IV) 90–91 4-fluorophenylthiophene 133 Ex4 based analogues 92–94 5-fluoropyridin-3-amine 261 pharmaceutical developments β-fragmentation 119 92 fremanezumab 202, 208, 210, 211 receptor binding and activation Friedel–Crafts acylation of 91–92 phenetole (PhOEt) 116 Glucagon 89–92, 100–102 Friedel–Crafts reaction 119, 125, D-gluconolactone 116, 119, 123, 133 125, 127, 130 FVIII-deficient plasma 227, 230, glucose tolerance test 102 234, 235 L-glutamic acid decarboxylase (GAD) 8–10 g C-glycoside 111, 117 G protein-coupled receptor, O-glucosides 111, 113–114, 133, calcitonin receptor-like 137 receptor (CALCRL) 199 glycine carbamate 258 GABA receptor agonists 8 glycosyl cross-coupling 117, 121 GABA uptake inhibitors 8 Gramicidin S 11, 12 galcanezumab 208, 210, 211 γ-aminobutyric acid h aminotransferase (GABA-AT) β-hairpin 68 8 hemophilia A plasma 234 glioblastoma U87 cells 254 heterocyclic replacements 280 GLP-1 receptor agonists high throughput screening (HTS) cardiovascular protective effects campaign 3, 250, 252, 267, 90 276–278 cryo EM structure 91 histonedeacetylase inhibitors discovery and compounds 93 27–29 exendin-4 90 homodimerized antibodies 232, GLP-1 based analogues 233 albiglutide and albenatide 100 hook effect 61 co-agonists 99–100 Huisgen 1,3-dipolar cycloaddition dulaglutide 98–99 reaction 57 liraglutide 95–96 Huisgen reaction 57 296 Index

human leukocyte antigens (HLA) preclinical characterization of 160, 164–165 261–262 human pregnane X receptor (hPXR) synthesis of 260–261 259–261 clinical studies 262 hydrochloride salt 6 crystal structure of 250 hydrophobic binding site 58, 59, implication 249 92 mIDH1 Inhibitors 250–252 hypoxia-inducible factor-1α structural analysis 251 (HIF-1α) 49–50, 55 j i JeKo-1 mantle cell lymphoma cell Immune suppressive tumor line 279, 281 microenvironment (TME) Jeko-1 mantle cell lymphoma 180 subcutaneous xenograft immunomodulatory drugs (IMiDs) model 281 50, 54, 64, 66–68, 70 incretin effect 89 k ⚪ incretins 89 Kisqali R (ribociclib) indisulam 68 cross-screening 277–282 3-indole 254 cyclin D1-CDK4 281 Institute for Clinical Economic disease background 273–274 Review (ICER) 208 drug discovery efforts 276 insulin 23–25, 89, 90, 94, 96, 100, early phase clinical studies 111, 113, 140, 142–145 283–284 interleukin-6 (IL-6) 174–175 fragment-based approach in vitro-in vivo correlations (IVIVC) 276–277 62 phase 3 clinical studies 284–285 5-iodo-2-methylbenzoic acid 133 target background and validation iodonium triflate 123 274–276 ion chromatography analysis 232 ipragliflozin 111, 125, 129–131, l 136–138, 141, 143–144 lead peptide 102 (S)-3-isobutyl-GABA 9 lenalidomide 5, 23, 50, 54, 55, 64, isocitrate 249–250 67 isocyanide 260–261 lentiviral vector-engineered T cell isopropylidene hydrolysis 124 products 177 isopropylmagnesium chloride 132 licogliflozin 113, 115, 141 ivosidenib ligandable proteome 71 AG-120 β-ligation 116 discovery of 257–260 liraglutide 95–96, 99 Index 297 lixisenatide 94 p luseogliflozin 123 Pacific Yew Act 16 paclitaxel 14–17 m palladium hydroxide 125, 128 major histocompatibility complex parallel artificial membrane (MHC) class 164 permeability assay (PAMPA) market capitalization 3 279 4-methoxy-2-methylbenzoic acid patent lifetime 4 124–125 Pd-mediated coupling 261 2-methoxypropene 127 pegylatedloxenatide 95 4-methyl GABA 9 peracetyl glucosylated methylaminophenyl analogs 254 benzophenone 119 N-methylmorpholine 119 persilylated D-gluconolactone 116, methylsulfanyl(tributyl)stannane 119 119 pharmacokinetics (PK) 62, 121, 5′-methylsulfanyl derivative 119 170, 227, 236, 240 mode of action (MoA) 22, 59–61, pharmacometric approach 238 66, 224, 267 phlorizin 113, 115 monoclonal antibodies 25–26, polar surface area (PSA) 50, 62, 200, 202, 208, 210, 212, 236 260 monovalent degraders 47, 64–71 poly-ubiquitination 48, 49 multiple myeloma 6, 23, 48, 50, pomalidomide 5, 50, 54–56, 67 67, 187 pregabalin 8–10 mustard gas 6, 7 proteasome inhibitors 22, 48 myelosupression 282 protein destabilizers 66 protein-coding genes 58 n Proteolix 23 N-terminus 100, 254 publicly funded organizations 3, new drug applications (NDAs) 4 197, 207 4-pyridyl 254 nitrogen-linked analogs 254 pyrrole 276 no observable adverse effect level pyrrolopyrimidinone 277 (NOAEL) 231, 234 r o radiation therapy 6 olcegepant 201, 204, 205 rapamycin 64, 65 overall response rate (ORR) 185, remogliflozin 111, 113, 133–137, 186, 265 142 (S)-5-oxopyrrolidine-2-carboxylic ribociclib 273, 277, 279–285 acid 261 rimegepant 204, 205, 207, 208 298 Index

rituximab 5, 25–26 streptomycin 11 rizatriptan 207 structural Genomix consortium 29 structure activity relationship (SAR) s 17, 19, 20, 32, 115, 250, 252, selective estrogen receptor degrader 254, 255, 257, 260, 267, 278 (SERD) 66 suberoylanilidehydroxamic acid semaglutide 96–98 (SAHA) 27–29 sitagliptin 91, 135, 142 sulfonylureas 113, 140 sodium-glucose linked transporter 2 sumatriptan 201, 208 (SGTL2) inhibitors sunitinib 32, 33 empagliflozin 113 gliflozin inhibitors t bexagliflozin 122–123 T cell receptor (TCR) 161–166 canagliflozin 130–133 antigen presenting cells (APCs) dapagliflozin 114–118 164 ertugliflozin 128–129 challenges with 165 ipragliflozin 129–130 clinical trials 162 luseogliflozin 123–125 complementary-determining remogliflozin 133–134 regions (CDRs) 163 sotagliflozin 119 costimulatory receptors 163 tofogliflozin 125–128 extracellular domains 163 mechanism of action 112–113 Human Leukocyte Antigens natural glucose reabsorption (HLA) 164 threshold 112 maturation process 162–163 safety profile and adverse events 141–143 T cell redirecting antibodies 233 type 2 diabetes treatment targeted protein degradation 47, application 143–144 48, 51, 53, 54, 57–60, 71 bodyweight reduction accumulation 59 140–141 amide-bond formation 57 cardioprotective effects 138 binary vs. ternary complex randomized controlled trials formation approaches 66 136 catalytic mode of action 60–61 renoprotective potential patient cellular retinoic acid-binding 139 proteins (CRABP-I and-II) sotagliflozin 111, 114, 119–121, 49 143, 144 CRBN ligands 55 O-spiroketal ring system 125 cytosolic 50 STELLA-LONG TERM trial 143 design and optimization 55 Index 299 disadvantages and limitations heterobifunctional molecules 62–64 55 druggable proteome 58–59 heterogeneous substrate E3 ligase cereblon 49 specificities 53 E3 ubiquitin ligase 48 Ikaros and Aiolos 54 event-driven pharmacology and K48 ubiquitin chains 53 prolonged PD effect 61 of lenalidomide and historical development 49 pomalidomide 54 Huisgen 1,3-dipolar cycloaddition RING E3s, HECT E3s and RBR reaction 57 E3s 53 MDM2 ligands 55 tissue-or compartment-specific MetAP2 protein 49 expression 54 molecular glue-like degraders and VHL ligands 55 monovalent degraders taspoglutide 97–98 conventional binary approaches Taxol 14–18 telcagepant 201, 202, 204, 205, 66 207, 210 CRBN degron-containing tenofovir 30, 31 proteins 70 1,1,3,3-tetramethyldisiloxane 133 CRBN neo-substrates 68 2,3,4,6-tetra-O-trimethylsilyl-β-D- event-driven pharmacology gluconolactone 133 66 thalidomide 5–6, 49, 67 FRB domain 65 thiazole 254 immunomodulatory drugs thiazolidinediones 113 (IMiDs) 66 C-thioglucosides 123 mode of action (MoA) 66 tociluzimab 185 phenotypic screening approach tofogliflozin 111, 125–129, 67 136–138, 141, 142 protein destabilizers 66 transmembrane domain (TMD) thalidomide analogs 68 59, 91, 92, 102, 103, 163, of neo-substrates 50 166–168 peptidic binding ligands 49 triethylsilane 116, 117, 120, 121, scaffolding functions 59–60 125, 127, 131, 132 target specificity 60 trimethylsilyl deprotection ubiquitin-proteasome system 121–122 (UPS) 48 trimethylsilyl triflate 119, 123 ubiquitin-proteasome system and TruvadaTM 30, 31 E3 ligases tumor 2-HG inhibition 256–259 bivalent degrader approach 54 tumor infiltrating lymphocytes CRBN expression 54 160 300 Index

u Ugi reaction 251–253, 256, 263, ubiquitin-proteasome system (UPS) 267, 273 48, 53–55, 63, 73 L-uronic acid 119 ubiquitination 48–50, 53, 57, 60, 62, 68, 70 v Ubrogepant 204, 205, 207, 208 VERTIS MET trial 136, 140, 142 Ugi four-component reaction 261 VHL-1 50, 51, 56