Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10593275 | Bioorganic & Medicinal Chemistry Letters | 2013 | 4 Pages |
Abstract
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.
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Authors
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. Jr., Taoues Temal, Minghan Wang,