2017-08-01·European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V2区 · 医学
Role of regional absorption and gastrointestinal motility on variability in oral absorption of a model drug.
2区 · 医学
作者: Ajit S Narang ; Anand Balakrishnan ; John Morrison ; Jinjiang Li ; Jennifer Wang ; Huidong Gu ; Katrina Taylor ; Kenneth Santone ; Jon Ehrmann ; Sophie Beyer ; Xujin Lu ; Rod Ketner ; Jennifer Pizzano ; Tami Orcutt ; Eric Shields ; Heidi Dulac ; Sharon Aborn ; Margaret Batchelder ; Kimberley Lentz
Variability in oral absorption in pre-clinical species makes human dose projection challenging. In this study, we investigated the mechanistic basis of variability in oral absorption of a model hydrophobic compound with pH-dependent solubility, BMS-955829, after oral dosing in rats, dogs, and cynomolgus monkeys. The contribution of regional absorption to pharmacokinetic variability was assessed in ported monkeys by direct intraduodenal and intraileal administration. The effect of BMS-955829 on gastric emptying and intestinal motility was investigated by radiography after co-administration of barium. BMS-955829 exhibited species dependent oral bioavailability, with high variability in monkeys. During regional absorption studies, highest rate of drug absorption was observed after direct intraduodenal administration. Radiography studies indicated that BMS-955829 slowed gastric emptying and intestinal motility. The effect of rate and site of drug release on oral exposure was studied using different drug product formulations. Reducing the rate of drug release reduced oral exposure variability without compromising exposure in cynomolgus monkeys. This effect was likely mediated by avoidance of rapid initial absorption and drug effect on gastric emptying and intestinal transit within the biorelevant timeframe. Thus, drug release rate can modulate the effect of physiological factors on variability in the oral absorption of sensitive compounds.
2016-03-10·ACS Medicinal Chemistry Letters3区 · 医学
Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5
3区 · 医学
作者: Yang, Fukang ; Snyder, Lawrence B. ; Balakrishnan, Anand ; Brown, Jeffrey M. ; Sivarao, Digavalli V. ; Easton, Amy ; Fernandes, Alda ; Gulianello, Michael ; Hanumegowda, Umesh M. ; Huang, Hong ; Huang, Yanling ; Jones, Kelli M. ; Li, Yu-Wen ; Matchett, Michele ; Mattson, Gail ; Miller, Regina ; Santone, Kenneth S. ; Senapati, Arun ; Shields, Eric E. ; Simutis, Frank J. ; Westphal, Ryan ; Whiterock, Valerie J. ; Bronson, Joanne J. ; Macor, John E. ; Degnan, Andrew P.
Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.