title: Antagonists of the calcium receptor I. Amino alcohol-based parathyroid hormone secretagogues.
abstract: Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC(50) = 11 microM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the beta-adrenergic receptor subtypes. These SAR studies ultimately led to the identification of 38 (NPS 2143; SB-262470A), a potent and orally active CaR antagonist. Pharmacokinetic characterization of 38 in the rat revealed that this molecule had a large volume of distribution (11 L/kg), which resulted in a prolonged systemic exposure, protracted increases in the plasma levels of PTH, and an overall lack of net bone formation effect in a rodent model of osteoporosis.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. Robert.W.Marquis@gsk.com
authors.forename: Robert W
authors.initials: RW
authors.lastname: Marquis
authors.forename: Amparo M
authors.initials: AM
authors.lastname: Lago
authors.forename: James F
authors.initials: JF
authors.lastname: Callahan
authors.forename: Robert E Lee
authors.initials: RE
authors.lastname: Trout
authors.forename: Maxine
authors.initials: M
authors.lastname: Gowen
authors.forename: Eric G
authors.initials: EG
authors.lastname: DelMar
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Van Wagenen
authors.forename: Sarah
authors.initials: S
authors.lastname: Logan
authors.forename: Scott
authors.initials: S
authors.lastname: Shimizu
authors.forename: John
authors.initials: J
authors.lastname: Fox
authors.forename: Edward F
authors.initials: EF
authors.lastname: Nemeth
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Theresa
authors.initials: T
authors.lastname: Roethke
authors.forename: Brian R
authors.initials: BR
authors.lastname: Smith
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.forename: John
authors.initials: J
authors.lastname: Lee
authors.forename: Richard M
authors.initials: RM
authors.lastname: Keenan
authors.forename: Pradip
authors.initials: P
authors.lastname: Bhatnagar
mesh_terms: D000284:Administration, Oral; D000605:Amino Alcohols / Q000737:chemistry* / Q000493:pharmacokinetics*; D000818:Animals; D006801:Humans; D010024:Osteoporosis / Q000188:drug therapy; D010281:Parathyroid Hormone / Q000097:blood*; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000605:Amino Alcohols; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing