RESUMEN
In a search for novel small molecule calcium-sensing receptor (CaSR) antagonists as oral bone anabolic agents, we discovered dihydrobenzofuran cyclopropane carboxylic acid derivatives, such as 12f (IC50=27.6nM), are highly potent calcium-sensing receptor antagonists. Studies in rats established that compound 12f stimulates parathyroid hormone (PTH) release in a fast-acting, pulsatile manner.
Asunto(s)
Benzofuranos/química , Ciclopropanos/metabolismo , Osteoporosis/tratamiento farmacológico , Receptores Sensibles al Calcio/antagonistas & inhibidores , Administración Oral , Animales , Benzofuranos/metabolismo , Benzofuranos/farmacocinética , Benzofuranos/uso terapéutico , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapéutico , Evaluación Preclínica de Medicamentos , Femenino , Semivida , Osteoporosis/patología , Hormona Paratiroidea/sangre , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/metabolismo , Relación Estructura-ActividadRESUMEN
The Ru(II) complexes of SDP and DPEN combined with t-BuOK in 2-propanol formed a very effective catalyst for the hydrogenation of simple aromatic ketones with high activity and enantioselectivity. The racemic alpha-arylcycloalkanones can also be hydrogenated by this system, providing alpha-arylcycloalkanols in excellent cis/trans stereoselectivity (>99:1) and enantioselectivity (up to 99.9%) for the cis isomer. In the study of the effect of the alkali metal cation in the hydrogenation of acetophenone using RuCl(2)(Tol-SDP)(DPEN) and RuCl(2)(Xyl-SDP)(DPEN) catalysts, we found that t-BuONa provided a faster reaction than t-BuOK, which indicated that the sterically hindered diphosphine ligands preferred the base with the smaller metal cation.