title: Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency.
abstract: A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2',6'-dimethyl-3'-pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK(i) = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK. alan.d.borthwick@drugmoldesign.com
authors.forename: Alan D
authors.initials: AD
authors.lastname: Borthwick
authors.forename: John
authors.initials: J
authors.lastname: Liddle
authors.forename: Dave E
authors.initials: DE
authors.lastname: Davies
authors.forename: Anne M
authors.initials: AM
authors.lastname: Exall
authors.forename: Christopher
authors.initials: C
authors.lastname: Hamlett
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: Hickey
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Mason
authors.forename: Ian E D
authors.initials: IE
authors.lastname: Smith
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Nerozzi
authors.forename: Simon
authors.initials: S
authors.lastname: Peace
authors.forename: Derek
authors.initials: D
authors.lastname: Pollard
authors.forename: Steve L
authors.initials: SL
authors.lastname: Sollis
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allen
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Woollard
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pullen
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Westfall
authors.forename: Dinesh J
authors.initials: DJ
authors.lastname: Stanislaus
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors; D054659:Diketopiperazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010121:Oxytocin / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D054659:Diketopiperazines; D009025:Morpholines; D018045:Receptors, Oxytocin; D010121:Oxytocin; C571185:epelsiban