title: Optimisation of pharmacokinetic properties to afford an orally bioavailable and selective V1A receptor antagonist.
abstract: The previously described lead compound 5 is a potent and selective V(1A) antagonist with affinity at both the rat and human receptor, but displays poor oral bioavailability and moderate clearance. We report herein the successful optimisation of the pharmacokinetic (PK) properties to afford the potent, selective, orally bioavailable and CNS penetrant compound 15f. A custom optimisation approach was required which demonstrated the value of using early, rapid in vivo PK studies to show improvements in oral exposure. Such assays may be of particular value where low oral bioavailability is anticipated to be multifactorial (e.g., permeability, gut wall metabolism and/or transport) where satisfactory modelling of in vitro data is likely to be difficult within a drug discovery context.
authors.affiliation: Department of Medicinal Chemistry, MSD, Newhouse, Motherwell, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Arbuckle
authors.forename: James
authors.initials: J
authors.lastname: Baker
authors.forename: David
authors.initials: D
authors.lastname: Barn
authors.forename: Matilda
authors.initials: M
authors.lastname: Bingham
authors.forename: Angus
authors.initials: A
authors.lastname: Brown
authors.forename: Kirsteen
authors.initials: K
authors.lastname: Buchanan
authors.forename: Mark
authors.initials: M
authors.lastname: Craighead
authors.forename: Richard
authors.initials: R
authors.lastname: Goodwin
authors.forename: Susan
authors.initials: S
authors.lastname: Goutcher
authors.forename: Michael
authors.initials: M
authors.lastname: Kiczun
authors.forename: Amanda
authors.initials: A
authors.lastname: Lyons
authors.forename: Rachel
authors.initials: R
authors.lastname: Milne
authors.forename: Brian
authors.initials: B
authors.lastname: Montgomery
authors.forename: Susan
authors.initials: S
authors.lastname: Napier
authors.forename: Jeremy
authors.initials: J
authors.lastname: Presland
authors.forename: Hazel
authors.initials: H
authors.lastname: Sloan
authors.forename: Zara
authors.initials: Z
authors.lastname: Turnbull
authors.forename: Grant
authors.initials: G
authors.lastname: Wishart
mesh_terms: D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001682:Biological Availability; D006801:Humans; D008297:Male; D010455:Peptides / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D010455:Peptides; D017483:Receptors, Vasopressin; D010649:Phenylalanine