title: Metabolism-guided design of short-acting calcium-sensing receptor antagonists.
abstract: As part of a strategy to deliver short-acting calcium-sensing receptor (CaSR) antagonists, the metabolically labile thiomethyl functionality was incorporated into the zwitterionic amino alcohol derivative 3 with the hope of increasing human clearance through oxidative metabolism, while delivering a pharmacologically inactive sulfoxide metabolite. The effort led to the identification of thioanisoles 22 and 23 as potent and orally active CaSR antagonists with a rapid onset of action and short pharmacokinetic half-lives, which led to a rapid and transient stimulation of parathyroid hormone in a dose-dependent fashion following oral administration to rats. On the basis of the balance between target pharmacology, safety, and human disposition profiles, 22 and 23 were advanced as clinical candidates for the treatment of osteoporosis.
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: James A
authors.initials: JA
authors.lastname: Southers
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Bauman
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Humphries
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Gayatri
authors.initials: G
authors.lastname: Balan
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: John F
authors.initials: JF
authors.lastname: Sagal
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Tristan S
authors.initials: TS
authors.lastname: Maurer
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Robert
authors.initials: R
authors.lastname: Oliver
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Michael
authors.initials: M
authors.lastname: Herr
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: David R
authors.initials: DR
authors.lastname: Healy
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Brendon
authors.initials: B
authors.lastname: Kapinos
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Gwendolyn D
authors.initials: GD
authors.lastname: Fate
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Riccardi
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Vishwas M
authors.initials: VM
authors.lastname: Paralkar
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Brown
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
keywords: CaSR antagonists; Calcium; PTH; cytochrome P450; metabolite; oxidation