Antagonists of the calcium receptor I. Amino alcohol-based parathyroid hormone secretagogues.
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.
Marquis
Robert W
RW
Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. Robert.W.Marquis@gsk.com
Lago
Amparo M
AM
Callahan
James F
JF
Trout
Robert E Lee
RE
Gowen
Maxine
M
DelMar
Eric G
EG
Van Wagenen
Bradford C
BC
Logan
Sarah
S
Shimizu
Scott
S
Fox
John
J
Nemeth
Edward F
EF
Yang
Zheng
Z
Roethke
Theresa
T
Smith
Brian R
BR
Ward
Keith W
KW
Lee
John
J
Keenan
Richard M
RM
Bhatnagar
Pradip
P
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
D000605:Amino Alcohols; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing