Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism
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- 作者：Paul M. Wehn ; Paul E. Harrington ; Timothy J. Carlson ; James Davis ; Pierre Deprez ; Christopher H. Fotsch ; Mark P. Grillo ; Jenny Ying-Lin Lu ; Sean Morony ; Kanaka Pattabiraman ; Steve F. Poon ; Jeff D. Reagan ; David J. St. Jean Jr. ; Taoues Temal ; Minghan Wang ; Yuhua Yang ; Charles Henley III ; Sarah E. Lively
- 关键词：Calcimimetics ; Positive allosteric modulators ; 1 ; 2 ; 4-Thiadiazoles ; Metabolite ID ; Time dependent inhibition
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：15 December, 2013
- 年：2013
- 卷：23
- 期：24
- 页码：6625-6628
- 全文大小：1163 K
文摘
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.