Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 24; pp. 6625 - 6628
• Main Authors: Wehn, Paul M., Harrington, Paul E., Carlson, Timothy J., Davis, James, Deprez, Pierre, Fotsch, Christopher H., Grillo, Mark P., Lu, Jenny Ying-Lin, Morony, Sean, Pattabiraman, Kanaka, Poon, Steve F., Reagan, Jeff D., St. Jean, David J., Temal, Taoues, Wang, Minghan, Yang, Yuhua, Henley, Charles, Lively, Sarah E.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2013; Elsevier
• Subjects: 1,2,4-Thiadiazoles; Administration, Oral; animal models; Animals; bioavailability; Biological Availability; Calcimimetics; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Half-Life; hyperparathyroidism; Hyperparathyroidism, Secondary - drug therapy; Hyperparathyroidism, Secondary - metabolism; Hyperparathyroidism, Secondary - pathology; Life Sciences & Biomedicine; Male; Metabolite ID; metabolites; Parathyroid Hormone - metabolism; pharmacokinetics; Pharmacology & Pharmacy; Physical Sciences; Positive allosteric modulators; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing - chemistry; Receptors, Calcium-Sensing - metabolism; Science & Technology; Thiazoles - chemistry; Thiazoles - pharmacokinetics; Thiazoles - therapeutic use; Time dependent inhibition; urea; Urea - analogs & derivatives; Positive allosteric modulators; Metabolite ID; Time dependent inhibition; Calcimimetics; 1,2,4-Thiadiazoles; PATHOGENESIS; CALCIUM-SENSING RECEPTOR; BIOACTIVATION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.10.050

A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.