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

• Published in: Bone (New York, N.Y.) Vol. 46; no. 2; pp. 534 - 542
• Main Authors: Kumar, Sanjay, Matheny, Christopher J, Hoffman, Sandra J, Marquis, Robert W, Schultz, Maggie, Liang, Xiaoguang, Vasko, Janice A, Stroup, George B, Vaden, Vernal R, Haley, Hyking, Fox, John, DelMar, Eric G, Nemeth, Edward F, Lago, Amparo M, Callahan, James F, Bhatnagar, Pradip, Huffman, William F, Gowen, Maxine, Yi, Bingming, Danoff, Theodore M, Fitzpatrick, Lorraine A
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.02.2010; Elsevier
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Bone and Bones - cytology; Bone and Bones - drug effects; Bone formation; Calcium - blood; Calcium-sensing receptor; Cell Proliferation - drug effects; Diseases of the osteoarticular system; Dogs; Drug Administration Schedule; Ethanolamines - administration & dosage; Ethanolamines - chemistry; Ethanolamines - pharmacokinetics; Ethanolamines - pharmacology; Fundamental and applied biological sciences. Psychology; Haplorhini; Humans; Male; Medical sciences; Naphthalenes - administration & dosage; Naphthalenes - chemistry; Naphthalenes - pharmacokinetics; Naphthalenes - pharmacology; Organ Size - drug effects; Orthopedics; Osteogenesis - drug effects; Osteoporosis; Osteoporosis. Osteomalacia. Paget disease; Ovariectomy; Parathyroid gland; Parathyroid Glands - cytology; Parathyroid Glands - drug effects; Parathyroid hormone; Parathyroid Hormone - blood; Phenylpropionates - administration & dosage; Phenylpropionates - chemistry; Phenylpropionates - pharmacokinetics; Phenylpropionates - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing - antagonists & inhibitors; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Parathyroid gland; Osteoporosis; Bone formation; Calcium-sensing receptor; Parathyroid hormone; Calcium; Diseases of the osteoarticular system; Calcium antagonist; Oral administration; Concentration; Blood plasma; Morphology; Parathyroid glands; Bone
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2009.09.028

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.