2 research outputs found
Indazole-6-phenylÂcyclopropylÂcarboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy
GPR120
agonists have therapeutic potential for the treatment of
diabetes, but few selective agonists have been reported. We identified
an indazole-6-phenylÂcyclopropylÂcarboxylic acid series
of GPR120 agonists and conducted SAR studies to optimize GPR120 potency.
Furthermore, we identified a (<i>S</i>,<i>S</i>)-cyclopropylÂcarboxylic acid structural motif which gave selectivity
against GPR40. Good oral exposure was obtained with some compounds
displaying unexpected high CNS penetration. Increased MDCK efflux
was utilized to identify compounds such as <b>33</b> with lower
CNS penetration, and activity in oral glucose tolerance studies was
demonstrated. Differential activity was observed in GPR120 null and
wild-type mice indicating that this effect operates through a mechanism
involving GPR120 agonism
Design and Optimization of Pyrazinecarboxamide-Based Inhibitors of Diacylglycerol Acyltransferase 1 (DGAT1) Leading to a Clinical Candidate Dimethylpyrazinecarboxamide Phenylcyclohexylacetic Acid (AZD7687)
A new series of pyrazinecarboxamide DGAT1 inhibitors
was designed to address the need for a candidate drug with good potency,
selectivity, and physical and DMPK properties combined with a low
predicted dose in man. Rational design and optimization of this series
led to the discovery of compound <b>30</b> (AZD7687), which
met the project objectives for potency, selectivity, in particular
over ACAT1, solubility, and preclinical PK profiles. This compound
showed the anticipated excellent pharmacokinetic properties in human
volunteers