RESUMEN
The design and profile of a series of zwitterionic calcium sensing receptor negative allosteric modulators is described. Evaluation of key analogues using a rat model demonstrate a robust response, significantly improved potency over ronacaleret and have the potential as an oral, anabolic treatment for osteoporosis.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Ciclopropanos/química , Indanos/química , Fenilpropionatos/química , Receptores Sensibles al Calcio/antagonistas & inhibidores , Administración Oral , Anabolizantes , Animales , Línea Celular , Ciclopropanos/farmacocinética , Ciclopropanos/farmacología , Descubrimiento de Drogas , Humanos , Indanos/farmacocinética , Indanos/farmacología , Microsomas Hepáticos , Osteoporosis/tratamiento farmacológico , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacología , RatasRESUMEN
Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series.
RESUMEN
The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.