Arylpropanolamines: selective beta3 agonists arising from strategies to mitigate phase I metabolic transformations.

Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective beta(3) agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01-2% of a very potent alpha(1) adrenergic agonist 2. A summary of the SAR for this hepatic microsomal conversion precedes presentation of strategies to maintain the advantages of chemotype 1 while mitigating the consequences of N-dealkylation. This effort led to the identification of 4-hydroxy-3-methylsulfonanilidopropanolamines 15 for which the SAR for the unique stereochemical requirements for binding to the beta adrenergic receptors culminated in the identification of the potent, selective beta(3) agonist 15f.

Pharmacokinetics of muraglitazar (BMS-298585), a dual peroxisome proliferator-activated receptors (PPAR) alpha and gamma activator, in mice, rats, dogs, and monkeys.

The pharmacokinetic parameters of muraglitazar, a novel dual-activator of the peroxisome proliferator-activated receptors (PPAR) alpha and gamma, were determined in mice, rats, dogs, and monkeys after intravenous and oral administration. In the mouse, rat, and monkey the absolute oral bioavailability of muraglitazar ranged from 64 to 88%, and in the dog oral bioavailability was approximately 18%. The systemic clearance values of muraglitazar in the mouse, rat, dog, and cynomolgus monkey were 1.2, 3.0, 12.3 and 1.2 ml min-1 kg-1, respectively. The terminal elimination half-life was 2.4 h in dogs and 7.3 h in rats. The terminal elimination half-life could not be determined in the mouse and monkey because the sampling interval did not adequately cover the terminal elimination phase. Muraglitazar appears to be distributed outside of the vasculature, with the steady-state volume of distribution being approximately twofold that of the vascular volume in rats and dogs, and approximately twofold that of the total body water in mice. The systemic plasma clearance of muraglitazar in humans was predicted to be approximately 12-14 ml min-1 kg-1 based on allometry or by scaling of in vitro clearance parameters. Overall, the pharmacokinetic parameters of muraglitazar in preclinical species were acceptable for the advancement of the compound as a clinical candidate.