509 Index a 4-(aminoalkoxy)benzylamines 262 Aβ peptide formation 478–480 aminobenzimidazoles 295–298 Abl inhibitor lapatinib 47 2-(4-aminophenoxy)naphthalene- acetazolamide 255 1,4-dione 140 acetylcholinesterase inhibitors 3-aminoquinazolinediones 7 core (AChEI) 256 scaffold 438 Acquired immune deficiency syndrome amoxapine 62–63 (AIDS) 15 amyloid cascade hypothesis 480 active pharmaceutical ingredients amyloid plaques (APIs) 104–105 Aβ peptide formation 478–480 activity-based protein profiling aggregation 480 (ABPP) 317 amyloid precursor protein (APP) 183 activity landscape modeling (ALM) ANAVEX1–41 498 19, 166 ANAVEX2–73 498 adenosine A2A receptor and adenosine ANAVEX3–71 (AF710B) 501 transporter 292–295 angiotensin converting enzyme (ACE) adenylosuccinate lyase (ASL/ADSL) 262, 415 317 angiotensin II (AII) 369 adverse drug reactions (ADRs) 8 angiotensin II type 1 (AT1)receptor afatinib 48 activity pathway 387–388 affinity purification-based MS (AP-MS) antagonist/PPARγ 377 approach 317 antagonists 372, 377 see also aldose reductase-related protein 2, angiotensin receptor blockers 317 (ARBs) allosteric SMKIs 47–48 antioxidant agents 384–386 α-carbonic anhydrase (CA) 161, 255 endothelins (ET) 372 Alzheimer’s disease 259 NO agents 382 amyloid cascade hypothesis structure of 370–372 480–481 angiotensin receptor blockers (ARBs) amyloid plaques 478–480 369, 372 metal toxicity 481–483 antihypertensive effects of 382 neurofibrillary tangles 481, 482 AT1 receptor 370 neuroinflammation 481–483 binding mode, AT1 372 oxidative stress 481–483 telmisartan 377 AMI-5 11 Drug Selectivity: An Evolving Concept in Medicinal Chemistry, First Edition. Edited by Norbert Handler and Helmut Buschmann. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2018 by Wiley-VCH Verlag GmbH & Co. KGaA. 510 Index angiotensin II receptor blockers (ARBs) 11β-hydroxysteroid dehydrogenase PPARγ agonists 415 type 1 (11β-HSD1) 423 6-anilinouracils (6-AUs) 461 β-ketoacyl-acyl carrier protein animal-based screening 80 (ACP) 454 antagonist see proliferator-activated β-lactam antibiotic 434 receptor-γ (PPARγ) β-lactam-fluoroquinolone hybrid AT1 377–382 molecules 458 ETA receptor 373 bicyclic diamines 450 antibacterial drugs 464–465 Bio Assay Ontology (BAO) 248 antibody/protein drug conjugates bioactivity data sources 248 brentuximab vedotin 219 Bio-Plex Pro magnetic cell signaling chances and challenges 218–219 assays 318 coltuximab ravtansine 222 blood–brain barrier (BBB) 60 effective therapeutic options 223 boronic acid-based glembatumumab vedotin 221 penicillin-binding-protein indatuximab ravtansine 222 inhibitors 452 inotuzumab ozogamicin 221 bradykinin B1 and B2 receptors lorvotuzumab mertansine 222 290–292 trastuzumab emtansine 220 breast cancer brain metastasis 59–62 antidepressant drugs 340–347 brentuximab vedotin 219 antinociceptive multitarget drugs 188 c antioxidant agents 384–386, 485 cancer proteins 60 antitarget receptors 10 cancer signaling bridge (CSB) 60 anti-trypanosomatid MTDL caproctamine 491 combined target/targeting approach cardiovascular diseases 262–264 149–151 catechol-O-methyltransferase (COMT) drug targeting approach 146–149 inhibitors 258 phenotypic approach 138–141 cathepsin-L (CatL) inhibitor 254 target-based approach 141, 143, 146 Cavbase 162 AP5346 (Pro-Lindac) 228 celecoxib 162 approved kinase inhibitors 36, 43–45, cell-based screening 80–81 48 cell phenotypic assays 3-AQD scaffold 439 high content imaging assays arylboronic acids 301–304 323–324 label-free cell phenotypic assays AT1/ETA receptor 374, 375 automated patch clamping 318 324–326 7-azaindole scaffold 165 reporter gene assays 322 cellular assays b automated patch clamping 318 BACE1 inhibitors/metal chelators chemogenomics-based assays 497–498 320–321 bacterialβ-glucuronidase (GUS) enzyme chemoproteomics-based assays 62 315–317 bacterial topoisomerases inhibitors 435 drug discovery 314–321 benextramine 491 high content imaging assays β-amyloid (Aβ) peptides 483 323–324 Index 511 label-free cell phenotypic assays Connectivity Map (cMap) 88 324–326 covalent inhibitors 48 ligand binding assays 314–315 covalent SMKIs 49 miniaturization 313 COX inhibitors 421–422 perspectives 326, 327 COX-2/sEH dual inhibitors 269 protein–protein interaction assays Critical Path initiative 107 319 crystallography/SAR 166–168 protein trafficking assays 319–320 cyclic guanosine monophosphate reporter gene assays 322 (cGMP) 382 signaling assays 317–318 cyclic nucleotide phosphodiesterases 3D organotypic culture 313 (PDEs) 163 cell viability assays 80 cyclooxygenase 2 (COX-2) 216 cephalosporin-based hybrid molecules 457–459 d cephalosporin-fluoroquinolones hybrid dabrafenib 45 molecules 457 Danish University Antidepressant cerulenin 454 Group (DUAG) 337 Chagas’ disease 137 dapoxetine 57–58 ChEMBL 248 dasatinib 59–62 chemical proteomics approach 140 depression 261–262 chemogenomics 16–18 diabetes and related metabolic diseases chemogenomics-based assays 264–267 320–321 1,4-disubstituted aromatic piperidines chemoinformatics 83–84 172 chemoproteomics-based assays disulfide linked drug conjugates 232 315–317 DNA-dependent protein kinase chiral drugs 111 (DNA-PK) 173 8-(3-chlorostyryl) caffeine 259 DNA gyrase 435 chronic myelogenous leukemia (CML) DNA topoisomerase inhibitors 435 112 DNA topoisomerase IV 435 ciprofloxacin 437, 445, 460 docking 82–83 cleavable linkers 231 doctor and patient 115–116 cobimetinib 47 donecopride 486 coltuximab ravtansine 222 dopamine type 2 (D2) antagonist 249 combinations of drugs 12 dopamine type 4 (D4) antagonist 249 competent patient 116 drug conjugates compound promiscuity 4 antibody/protein 217–223 computational and systematic drug enhanced permeation and retention repositioning 234 methods based on genome-wide linker chemistry 229–233 association study 66 polymer 223–229 methods based on knowledge of side preclinical and clinical development effects 64–65 208 methods based on transcriptomics small molecule 209 data 65–66 targeted delivery 209, 233 Computational Conformer Selection therapeutic efficacy 233 (CSS) approach 84 therapeutic opportunities 235 512 Index drug discovery dual COX-2/LTA4H inhibitor 268 anti-trypanosomatid MTDL, see dual FMS/KIT kinase inhibitors 165 anti-trypanosomatid MTDL dual GPR119 and DPP-IV MML 267 concept of selectivity 151 dual H3 and SERT modulator 263 GPCRs 135 dual HDAC and IMPDH inhibitors neglected tropical diseases (NTDs) 253 136–138, 143 dual MMP-1/CatL inhibitors 254 one-molecule-one-target paradigm dual MMP-2/CA IX inhibitors 255 136 dual NK1 receptor antagonist 262 drug repositioning dual pharmacophores amoxapine 62–63 cephalosporin-based hybrid computational and systematic molecules 457–459 64–68 fluoroquinolizine–rifamycin hybrid dapoxetine 57–58 drugs 462 dasatinib 59–62 fluoroquinolone–aminouracil hybrid duloxetine 58–59 drugs 461–462 list of repositioned drug 56, 57 fluoroquinolone–oxazolidinone perspective 68, 73 hybrid drugs 459–461 sildenafil 58 limitations and perspectives 463–464 sunitinib 59–62 dual phosphoinositide 3-kinase (PI3K)/ thalidomide 59 mammalian target of rapamycin drug repurposing 11 (mTOR) inhibitor 43 animal-based screening 80 dual PI3K/Tyr kinase inhibitors 167 cell-based screening 80–81 dual SERT and 5-HT1A modulator 261 chemoinformatics 83–84 dual TS/DHFR inhibitors 179 docking 82–83 duloxetine 58–59 drug-and protein-centric approach 86 mining of big data 88–89 e network pharmacology 86–88 EC0746 211 protein binding site 84–86 electroconvulsive therapy (ECT) 337 target-based screening 81–82 electronic health 115 drug selectivity 113–114 electronic medical records drug targeting 146–149 (EMRs) 82 druggable enzymes 434 endothelial dysfunction 384 DrugMap Central 87 endothelial growth factor (EGFR) DU-125530 351 inhibitor imatinib 46, 47 endothelin-A receptor (ET ) dual A2A and MAO-B inhibitor 260 A dual acetylcholinesterase antagonists 264 inhibitors-histamine H3 receptor endothelin (ET) receptor 372 antagonists 297–299 AT1 receptor 373 dual AChE and MAO-B inhibitors 258 Merck AII antagonist 372 dual AChEI and AChEI-induced SHR 375 beta-amyloid aggregation 257 DARAs 373, 374 dual-action receptor antagonist enzymatically cleavable linkers 232 (DARAs) 373, 375 E-pharmacophore based virtual dual aromatase–STS inhibitor 252 screening 299–301 Index 513 epigenetic relevant chemical space Gram-negative ParE 449 (ERCS) 14–15 green fluorescent protein (GFP) 319 epigenetics 13–14 GSK2140944 444 erythema nodosum laprosum (ENL) GyrA amino acids 443 59 GyrA/ParC antibacterials 445 eukaryotic SMKIs 38 GyrB/ParE inhibitors 446 EZN-2208 228 Gyrase/topoIV ATPase inhibition and antibacterial activity 447 f farnesoid X receptor (FXR) 299 h FDA-approved inhibitors 44 haptophore 147 flibanserin 347 hCB2R ligands 295–297 fluoroquinolizine–rifamycin hybrid high confidence protein pathways drugs 462 (HCPP) 60 fluoroquinolone–aminouracil hybrid high content imaging assays 323, 324 drugs 461–462 high content screening (HCS) 323 fluoroquinolone–oxazolidinone hybrid histamine H3 receptor antagonists drugs 459–461 262 fluoxetine (Prozac) 58 histone deacetylases (HDACs) 252 folate receptor (FR) positive HLA20 485 cells 211 HLA20A 485 form fits function 83 5-HT1F receptor 356 forward pharmacology 79 5-HT2A receptors 345 fragment-based drug design 250 antagonist 349 frequently used linkers 231 inhibition 345 5-HT6 receptor 356 g human acetylcholinesterase γ-secretase and PPARγ 496–497 (hAChE) 485 GAPDH 143 human African trypanosomiasis gefitinib 46 (HAT) 136 gene surgery 109 human AT1 receptor 370 gene therapy 108–110 human butyrylcholinesterase Generally Recognized