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

Abstract A series of urea based calcimimeticswas optimized for potencyand oral bioavailability. Crucial to this process was overcoming the poor pharmacokineticproperties of lead thiazole1 . 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. Calcimimetic18 exhibited excellent in vivo potencyin a 5/6 nephrectomized rat model and cross-species pharmacokinetics.