title: 2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics.
abstract: A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pK(i) > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2',4'-difluorophenyldiketopiperazine derivative 37, a highly potent oxytocin antagonist against the human oxytocin receptor (pK(i) = 8.9) that has >1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR(10) = 0.44 mg/kg iv).
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K. alan.d.borthwick@gsk.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: 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: 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: Paul G
authors.initials: PG
authors.lastname: Wyatt
mesh_terms: D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012709:Serum Albumin / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects; D014668:Vasotocin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D010879:Piperazines; D018045:Receptors, Oxytocin; D012709:Serum Albumin; C047046:atosiban; D014668:Vasotocin