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An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation.

Abstract：

: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.

journal_name

Bone

journal_title

Bone

authors

Kumar S,Matheny CJ,Hoffman SJ,Marquis RW,Schultz M,Liang X,Vasko JA,Stroup GB,Vaden VR,Haley H,Fox J,DelMar EG,Nemeth EF,Lago AM,Callahan JF,Bhatnagar P,Huffman WF,Gowen M,Yi B,Danoff TM,Fitzpatrick LA

doi

10.1016/j.bone.2009.09.028

subject

Has Abstract

pub_date

2010-02-01 00:00:00

pages

534-42

issue

2

eissn

8756-3282

issn

1873-2763

pii

S8756-3282(09)01937-1

journal_volume

46

pub_type

杂志文章,随机对照试验

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