Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds PDF
Preview Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds
FlorencioZaragozaDo¨rwald LeadOptimization forMedicinalChemists RelatedTitles Smith,D.A.,Allerton,C.,Kalgutkar,A.S., Curry,S.H.,Whelpton,R. vandeWaterbeemd,H.,Walker,D.K. DrugDisposition and Pharmacokinetics andMetabolism Pharmacokinetics inDrugDesign FromPrinciplestoApplications 2012 2011 ISBN:978-3-527-32954-0 ISBN:978-0-470-68446-7 Gad,S.C.(ed.) Rankovic,Z.,Morphy,R. DevelopmentofTherapeutic LeadGeneration Approaches Agents Handbook in DrugDiscovery 2012 2010 ISBN:978-0-471-21385-7 ISBN:978-0-470-25761-6 Tsaioun,K.,Kates,S.A.(eds.) Han,C.,Davis,C.B.,Wang,B.(eds.) ADMET forMedicinalChemists Evaluation ofDrugCandidates APracticalGuide forPreclinicalDevelopment Pharmacokinetics,Metabolism, 2011 Pharmaceutics,andToxicology ISBN:978-0-470-48407-4 2010 ISBN:978-0-470-04491-9 Sotriffer,C.(ed.) Virtual Screening Faller,B.,Urban,L.(eds.) Principles,Challenges,andPractical Guidelines HitandLeadProfiling 2011 IdentificationandOptimization ISBN:978-3-527-32636-5 ofDrug-likeMolecules 2009 ISBN:978-3-527-32331-9 Florencio Zaragoza Do¨rwald Lead Optimization for Medicinal Chemists Pharmacokinetic Properties of Functional Groups and Organic Compounds TheAuthor (cid:1) AllbookspublishedbyWiley-VCHare carefullyproduced.Nevertheless,authors, Dr.FlorencioZaragozaD¨orwald editors,andpublisherdonotwarrantthe LonzaAG informationcontainedinthesebooks, Rottenstrasse6 includingthisbook,tobefreeoferrors. 3930Visp Readersareadvisedtokeepinmindthat Switzerland statements,data,illustrations,procedural detailsorotheritemsmayinadvertentlybe Coverillustration: inaccurate. MobileinthestyleofAlexanderCalder. LibraryofCongressCardNo.:appliedfor BritishLibraryCataloguing-in-Publication Data Acataloguerecordforthisbookisavailable fromtheBritishLibrary. Bibliographicinformationpublishedby theDeutscheNationalbibliothek TheDeutscheNationalbibliothekliststhis publicationintheDeutsche Nationalbibliografie;detailedbibliographic dataareavailableontheInternetat <http://dnb.d-nb.de>. 2012Wiley-VCHVerlag&Co.KGaA, Boschstr.12,69469Weinheim,Germany Allrightsreserved(includingthoseof translationintootherlanguages).Nopartof thisbookmaybereproducedinany form–byphotoprinting,microfilm,orany othermeans–nortransmittedortranslated intoamachinelanguagewithoutwritten permissionfromthepublishers.Registered names,trademarks,etc.usedinthisbook, evenwhennotspecificallymarkedassuch, arenottobeconsideredunprotectedbylaw. Cover Adam-Design,Weinheim Typesetting: LaserwordsPrivateLimited, Chennai,India PrintingandBinding: StraussGmbH, Mo¨rlenbach,Germany Printedonacid-freepaper PrintISBN:978-3-527-33226-7 ePDFISBN:978-3-527-64566-4 oBookISBN:978-3-527-64564-0 ePubISBN:978-3-527-64565-7 MobiISBN:978-3-527-64567-1 V Contents Introduction XIII GlossaryandAbbreviations XV PartI Introduction 1 1 TheDrugDiscoveryProcess 3 1.1 Pharmacokinetics–StructureRelationship 5 1.2 TheFutureofSmall-MoleculeDrugs 9 References 11 2 LeadOptimization 13 2.1 WhatLimits/ReducesOralBioavailability? 14 2.2 WhatLimits/ReducesPlasmaHalf-Life? 15 2.3 HowtoImprovebbb-Penetration? 16 2.4 HowtoAvoidCYPInhibition/Induction? 16 2.5 HowtoAvoidInteractionwiththeHuman Ether-a`-go-go-RelatedGene(hERG)? 17 2.6 HowtoPreventToxicity? 17 2.7 ExamplesofPK-OptimizationinAnimals 20 2.7.1 DihydroorotateDehydrogenaseInhibitors 20 2.7.2 MatrixMetalloproteinaseInhibitors 21 2.7.3 AntibacterialAminobenzenesulfonamides 21 2.7.4 TyrosineKinaseInhibitors 22 2.7.5 5-HT Agonists 23 1A 2.7.6 DipeptidylPeptidaseIVInhibitors;StructuralVariationsofSitagliptin 23 2.7.7 P-SelectinInhibitors 24 2.7.8 β -AdrenergicAgonists 24 3 2.7.9 Vanilloid-1Antagonists 25 2.7.10 HIVProteaseInhibitors 25 2.7.11 MatrixMetalloproteinaseInhibitors(TestedinRats) 26 2.7.12 HIVIntegraseInhibitors 26 2.7.13 DopamineD Antagonists 27 3 2.7.14 InhibitorsofSolubleEpoxideHydrolase(TestedinMice,po) 28 VI Contents 2.7.15 Melanin-ConcentratingHormoneReceptor-1Antagonists 29 References 29 PartII ThePharmacokineticPropertiesofCompoundClasses 33 3 Alkanes 35 3.1 Metabolism 36 References 39 4 AlkenesandAlkynes 40 4.1 Metabolism 40 References 44 5 Arenes 45 5.1 Metabolism 45 6 Halides 49 6.1 Fluorine 49 6.2 Chlorine 51 6.3 Bromine 53 6.4 Iodine 53 6.5 AlkylatingAgents 54 Reference 55 7 Azides 58 8 NitroCompounds 59 8.1 Metabolism 60 9 AzoCompounds 62 10 Triazenes 64 11 NitratesandNitrites 66 FurtherReading 67 12 N-NitrosoCompounds 68 13 N-Oxides 70 14 Alcohols 71 14.1 Metabolism 72 Contents VII 15 Phenols 82 References 84 16 Ethers 91 16.1 Metabolism 92 Reference 93 17 Epoxides 96 18 Peroxides 97 19 Thiols 98 20 Thioethers 100 20.1 Metabolism 101 Reference 103 21 Sulfoxides 104 22 Sulfones 106 23 AliphaticAmines 107 23.1 Basicity 110 23.2 Metabolism 110 23.3 RatesofN-Dealkylation 112 Reference 114 24 QuaternaryAmmoniumSalts 118 Reference 119 25 Amidines 120 Reference 121 26 Guanidines,Acylguanidines,andBiguanides 122 26.1 Acylguanidines 123 26.2 Biguanides 123 Reference 124 27 Anilines 133 27.1 Metabolism 135 28 Hydrazines,Acylhydrazines,andHydrazones 137 VIII Contents 29 Aldehydes 138 30 Ketones 139 31 CarboxylicAcids 144 31.1 Metabolism 145 31.2 BioisosteresofCarboxylicAcids 146 31.3 AminoCarboxylicAcids,N-AcylAminoAcids, andRelatedCompounds 147 References 148 32 CarboxylicEsters 164 Reference 165 33 Amides 166 34 LactamsandImides 172 34.1 PyrazoloneAntipyretics 172 34.2 Five-MemberedLactamsasNootropics 173 References 174 35 Nitriles 184 References 185 36 Carbonates 186 37 Carbamates 187 37.1 CarbamatesasHypnotics 188 References 189 38 Ureas 192 Reference 193 39 ThiocarbonylCompounds 201 40 SulfonicAcids 203 41 SulfonicEsters 206 42 SulfatesandSulfamicAcids 207 43 PhosphonicAcids 209 Contents IX 44 PhosphoricAcidDerivatives 213 45 N-(Aminoalkyl)benzamides,-Benzoates,andRelatedCompounds 215 Reference 216 46 Arylalkylamines 225 46.1 Antihistaminics:History 225 Reference 226 47 Phenethylamines(2-Phenylethylamines) 267 47.1 BiologicalActivityofPhenethylamines 267 47.2 Metabolism 268 47.3 TetrahydroisochinolinesandRelatedCompounds 269 FurtherReading 270 48 AminoalkylindolesandIndoleAlkaloids 291 Reference 291 49 Phenothiazines 301 49.1 Metabolism 302 References 302 50 DibenzazepinesandRelatedTricyclicCompounds 310 51 3-Aryloxy-2-Hydroxypropylamines (β-AdrenergicAntagonists;‘‘β-Blockers’’) 320 51.1 Metabolism 320 52 Opiates 329 Reference 329 53 N-(Carboxyalkyl)-α-AminoAcidAmides(Prils) 335 Reference 336 54 AnilidesandAmidesofGlycine 341 55 Peptides,Peptidomimetics,andRelatedOligoamides 347 55.1 Peptidomimetics 348 55.2 ThrombinInhibitorsandRelatedCompounds 349 References 350 X Contents 56 Oligoarylamines,Oligoarylamides,Oligoarylcarbamates, andOligoarylureas 365 References 365 57 Imidazoles 377 References 378 58 Triazoles 387 59 Pyridines,Pyrimidines,andRelatedCompounds 393 59.1 ProtonPumpInhibitors 396 References 397 60 Quinolines 412 60.1 Tecans 415 60.2 Quinazolines 415 References 416 61 NucleosideAnalogs 428 Reference 428 62 Dihydropyridines 446 63 Arenesulfonamides 450 63.1 Antibacterials 450 63.2 Diuretics 450 Reference 451 64 Sulfonylureas 462 65 Benzodiazepines 466 Reference 467 66 Steroids 477 References 478 67 Anthracyclines 492 68 Arylacetic,Benzoic,andRelatedCarboxylicAcids(NSAIDS) 497 68.1 Salicylates 497 References 498
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