RESUMEN
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.
Asunto(s)
Hiperparatiroidismo Secundario/tratamiento farmacológico , Tiazoles/química , Tiazoles/uso terapéutico , Urea/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Semivida , Hiperparatiroidismo Secundario/metabolismo , Hiperparatiroidismo Secundario/patología , Masculino , Hormona Paratiroidea/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/química , Receptores Sensibles al Calcio/metabolismo , Tiazoles/farmacocinéticaRESUMEN
Following the identification of trisubstituted ureas as a promising new chemical series of allosteric modulators of the calcium sensing receptor (CaSR), we further explored the SAR around the urea substitution, leading to the discovery of benzothiazole urea compound 13. This compound is a potent calcimimetic with an EC50=20 nM (luciferase assay). Evaluated in an in vivo model of chronic renal failure (short term and long term in 5/6 nephrectomized rats), benzothiazole urea 13 significantly decreased PTH levels after oral administration while keeping calcemia within the normal range.
Asunto(s)
Benzotiazoles/química , Benzotiazoles/farmacología , Calcio/química , Receptores Sensibles al Calcio/antagonistas & inhibidores , Urea/análogos & derivados , Urea/farmacología , Benzotiazoles/síntesis química , Urea/síntesis química , Urea/químicaRESUMEN
Starting from Fendiline and R-568, we identified a novel series of urea compounds as positive allosteric modulators of the calcium sensing receptor (CaSR), as part of a program to identify novel therapeutics for secondary hyperparathyroidism. Initially identified disubstituted ureas were converted to trisubstituted urea lead 20e, which was further modified to increase in vivo potency. Replacing a carbomethoxy substituent by various bioisosteres led to compound 46 which exhibited potent in vitro and in vivo activity after oral administration.