An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation.
Daily subcutaneous administration of exogenous parathyroid hormone (PTH) promotes bone formation in patients with osteoporosis. Here we describe two novel, short-acting calcium-sensing receptor antagonists (SB-423562 and its orally bioavailable precursor, SB-423557) that elicit transient PTH release from the parathyroid gland in several preclinical species and in humans. In an ovariectomized rat model of bone loss, daily oral administration of SB-423557 promoted bone formation and improved parameters of bone strength at lumbar spine, proximal tibia and midshaft femur. Chronic administration of SB-423557 did not increase parathyroid cell proliferation in rats. In healthy human volunteers, single doses of intravenous SB-423562 and oral SB-423557 elicited transient elevations of endogenous PTH concentrations in a profile similar to that observed with subcutaneously administered PTH. Both agents were well tolerated in humans. Transient increases in serum calcium, an expected effect of increased parathyroid hormone concentrations, were observed post-dose at the higher doses of SB-423557 studied. These data constitute an early proof of principle in humans and provide the basis for further development of this class of compound as a novel, orally administered bone-forming treatment for osteoporosis.
GlaxoSmithKline, UM 2230, 709 Swedeland Road, King of Prussia, PA 19406-2711, USA.
Sanjay
S
Kumar
Christopher J
CJ
Matheny
Sandra J
SJ
Hoffman
Robert W
RW
Marquis
Maggie
M
Schultz
Xiaoguang
X
Liang
Janice A
JA
Vasko
George B
GB
Stroup
Vernal R
VR
Vaden
Hyking
H
Haley
John
J
Fox
Eric G
EG
DelMar
Edward F
EF
Nemeth
Amparo M
AM
Lago
James F
JF
Callahan
Pradip
P
Bhatnagar
William F
WF
Huffman
Maxine
M
Gowen
Bingming
B
Yi
Theodore M
TM
Danoff
Lorraine A
LA
Fitzpatrick
D000284:Administration, Oral; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects; D002118:Calcium / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004334:Drug Administration Schedule; D004983:Ethanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D010280:Parathyroid Glands / Q000166:cytology / Q000187:drug effects; D010281:Parathyroid Hormone / Q000097:blood*; D010666:Phenylpropionates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*
D004983:Ethanolamines; D009281:Naphthalenes; D010281:Parathyroid Hormone; D010666:Phenylpropionates; D044169:Receptors, Calcium-Sensing; C548825:SB 423562; D002118:Calcium