title: 2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 3. Synthesis, pharmacokinetics, and in vivo potency.
abstract: A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.
authors.affiliation: Department of Medicinal Chemistry, Cardiovascular and Urogenital Centre of Excellence for Drug Discovery, Stevenage, UK. alan.d.borthwick@drugmoldesign.com
authors.forename: Alan D
authors.initials: AD
authors.lastname: Borthwick
authors.forename: Dave E
authors.initials: DE
authors.lastname: Davies
authors.forename: Anne M
authors.initials: AM
authors.lastname: Exall
authors.forename: Richard J D
authors.initials: RJ
authors.lastname: Hatley
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Hughes
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Irving
authors.forename: David G
authors.initials: DG
authors.lastname: Livermore
authors.forename: Steve L
authors.initials: SL
authors.lastname: Sollis
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Nerozzi
authors.forename: Klara L
authors.initials: KL
authors.lastname: Valko
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allen
authors.forename: Marion
authors.initials: M
authors.lastname: Perren
authors.forename: Shalia S
authors.initials: SS
authors.lastname: Shabbir
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Woollard
authors.forename: Mark A
authors.initials: MA
authors.lastname: Price
mesh_terms: D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001667:Binding, Competitive; D001682:Biological Availability; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects
chemical_list: C513156:2-(2,4-difluorophenyl)-2-(3-(2,3-dihydro-1H-inden-2-yl)-6-(2-methylpropyl)-2,5-dioxo-1-piperazinyl)-N,N-dimethylethanamide; D065092:Antidiuretic Hormone Receptor Antagonists; D007192:Indenes; D010879:Piperazines; D018045:Receptors, Oxytocin; D010121:Oxytocin