ABSTRACT:Saxagliptin is a potent, selective, reversible dipeptidyl peptidase 4 (DPP4) inhibitor specifically designed for extended inhibition of the DPP4 enzyme and is currently under development for the treatment of type-2 diabetes. The pharmacokinetics of saxagliptin were evaluated in rats, dogs, and monkeys and used to predict its human pharmacokinetics. Saxagliptin was rapidly absorbed and had good bioavailability (50-75%) in the species tested. The plasma clearance of saxagliptin was higher in rats (115 ml/min/kg) than in dogs (9.3 ml/min/kg) and monkeys (14.5 ml/min/kg) and was predicted to be low to moderate in humans. The plasma elimination half-life was between 2.1 and 4.4 h in rats, dogs, and monkeys, and both metabolism and renal excretion contributed to the overall elimination. The primary metabolic clearance pathway involved the formation of a significant circulating, pharmacologically active hydroxylated metabolite, M2. The volume of distribution values observed in rats, dogs, and monkeys (1.3-5.2 l/kg) and predicted for humans (2.7 l/kg) were greater than those for total body water, indicating extravascular distribution. The in vitro serum protein binding was low (<30%) in rats, dogs, monkeys, and humans. After intra-arterial administration of saxagliptin to Sprague-Dawley and Zucker diabetic fatty rats, higher levels of saxagliptin and M2 were observed in the intestine (a proposed major site of drug action) relative to that in plasma. Saxagliptin has prolonged pharmacodynamic properties relative to its plasma pharmacokinetic profile, presumably due to additional contributions from M2, distribution of saxagliptin and M2 to the intestinal tissue, and prolonged dissociation of both saxagliptin and M2 from DPP4.

With the advent of polytherapy, drug interactions have become a common clinical problem. Although in vitro data are routinely used for the prediction of drug interactions, in vitro systems are not dynamic and sometimes fail to predict drug interactions. We sought to use the rat as an in vivo screening model to predict pharmacokinetic interactions with ketoconazole. The pharmacokinetic studies were conducted following an oral dose of CYP3A substrates and an optimized oral regimen of ketoconazole. In vitro reaction phenotyping was conducted using individual human and rat cDNA-expressed CYP enzymes and human or rat liver microsomes in the presence of ketoconazole. The in vitro experiments indicated that the test compounds were largely metabolized by CYP3A in both human and rat. The compounds could be rank-ordered with respect to the increase in C(max) and area under the curve (AUC) values relative to midazolam in the presence of ketoconazole. The degree of pharmacokinetic interaction with ketoconazole was dependent, in part, upon their in vitro metabolism in the presence of rat CYP3A1/3A2 and in rat and human microsomes, co-incubated with ketoconazole, and on their fraction metabolized (f(m)) in the rat relative to other disposition pathways. Based on the rank-order of interaction, the compounds could be prioritized for further preclinical development.

Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).

High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.