Antagonists of the calcium receptor. 2. Amino alcohol-based parathyroid hormone secretagogues.
When administered as a single agent to rats, the previously reported calcium receptor antagonist 3 elicited a sustained elevation of plasma PTH resulting in no increase in overall bone mineral density. The lack of a bone building effect for analogue 3 was attributed to the large volume of distribution (V(dss)(rat) = 11 L/kg), producing a protracted plasma PTH profile. Incorporation of a carboxylic acid functionality into the amino alcohol template led to the identification of 12 with a lower volume of distribution (V(dss)(12) = 1.18 L/kg) and a shorter half-life. The zwitterionic nature of antagonist 12 necessitated the utility of an ester prodrug approach to increase overall permeability. Antagonist 12 elicited a rapid and transient increase in circulating levels of PTH following oral dosing of the ester prodrug 11 in the dog. The magnitude and duration of the increases in plasma levels of PTH would be expected to stimulate new bone formation.
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
Rahman
Attiq
A
Dong
Xiaoyang
X
Stroup
George B
GB
Hoffman
Sandra
S
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
Roethke
Theresa
T
Smith
Brian R
BR
Ward
Keith W
KW
Bhatnagar
Pradip
P
D000284:Administration, Oral; D000605:Amino Alcohols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004285:Dogs; D004952:Esters; D006801:Humans; D010281:Parathyroid Hormone / Q000097:blood* / Q000378:metabolism; D010539:Permeability; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011412:Propanolamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C545535:3-(3-cyano-4-((3-((1,1-dimethyl-2-(2-naphthalenyl)ethyl)amino)-2-hydroxypropyl)oxy)phenyl)propanoic Acid; D000605:Amino Alcohols; D004952:Esters; D010281:Parathyroid Hormone; D010666:Phenylpropionates; D011355:Prodrugs; D011412:Propanolamines; D044169:Receptors, Calcium-Sensing; D002118:Calcium