title: Multiparameter optimization in CNS drug discovery: design of pyrimido[4,5-d]azepines as potent 5-hydroxytryptamine 2C (5-HT₂C) receptor agonists with exquisite functional selectivity over 5-HT₂A and 5-HT₂B receptors.
abstract: A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.
authors.affiliation: Discovery Chemistry, ‡Discovery Biology, and §Pharmacokinetics, Dynamics and Metabolism, Sandwich Laboratories, Pfizer Global Research and Development , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: R Ian
authors.initials: RI
authors.lastname: Storer
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.forename: Alan D
authors.initials: AD
authors.lastname: Brown
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bungay
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Conlon
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Corbett
authors.forename: Robert P
authors.initials: RP
authors.lastname: DePianta
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.forename: Danny K H
authors.initials: DK
authors.lastname: Ho
authors.forename: Alan S
authors.initials: AS
authors.lastname: Jessiman
authors.forename: Gordon
authors.initials: G
authors.lastname: McMurray
authors.forename: Cesar Augusto F
authors.initials: CA
authors.lastname: de Oliveira
authors.forename: Lee R
authors.initials: LR
authors.lastname: Roberts
authors.forename: James A
authors.initials: JA
authors.lastname: Root
authors.forename: Veerabahu
authors.initials: V
authors.lastname: Shanmugasundaram
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shapiro
authors.forename: Melanie
authors.initials: M
authors.lastname: Skerten
authors.forename: Dominique
authors.initials: D
authors.lastname: Westbrook
authors.forename: Simon
authors.initials: S
authors.lastname: Wheeler
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Whitlock
authors.forename: John
authors.initials: J
authors.lastname: Wright
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D002491:Central Nervous System Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003412:Cricetulus; D004285:Dogs; D015195:Drug Design; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D010539:Permeability; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014550:Urinary Incontinence, Stress / Q000188:drug therapy
chemical_list: C000591348:2-(difluoro(phenyl)methyl)-N-methyl-6,7,8,9-tetrahydro-5H-pyrimido(4,5-d)azepin-4-amine; C000591347:2-benzyl-9-methyl-4-(methylamino)-5,6,8,9-tetrahydro-7H-pyrimido(4,5-d)azepine; D001381:Azepines; D002491:Central Nervous System Agents; D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists