Vol. 30, Issue 7, 771-777, July 2002

The Pharmacokinetics of a Thiazole Benzenesulfonamide ₃-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability

Ralph A. Stearns, Randy R. Miller, Wei Tang, Gloria Y. Kwei, Frank S. Tang, Robert J. Mathvink, Elizabeth M. Naylor, Dawn Chitty, Vincent J. Colandrea, Ann E. Weber, Adria E. Colletti, John R. Strauss, Carol Ann Keohane, William P. Feeney, Susan A. Iliff, and Shuet-Hing Lee Chiu

Departments of Drug Metabolism (R.A.S., R.R.M., W.T., A.E.C., F.S.T., C.A.K., S-H.L.C.), Medicinal Chemistry (R.J.M., E.M.N., D.C., V.J.C., A.E.W.), Comparative Medicine (W.P.F., J.R.S., S.A.I.), and Pharmaceutical Research and Development (G.Y.K.), Merck Research Laboratories, Rahway, New Jersey

The pharmacokinetics and oral bioavailability of (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethylphenyl]thiazol-2-yl]benzenesulfonamide (1), a 3-pyridyl thiazole benzenesulfonamide ₃-adrenergic receptor agonist, were investigated in rats, dogs, and monkeys. Systemic clearance was higher in rats (~30 ml/min/kg) than in dogs and monkeys (both ~10 ml/min/kg), and oral bioavailability was 17, 27, and 4%, respectively. Since systemic clearance was 25 to 40% of hepatic blood flow in these species, hepatic extraction was expected to be low, and it was likely that oral bioavailability was limited either by absorption or a large first-pass effect in the gut. The absorption and excretion of ³H-labeled 1 were investigated in rats, and only 28% of the administered radioactivity was orally absorbed. Subsequently, the hepatic extraction of 1 was evaluated in rats (30%) and monkeys (47%). The low oral bioavailability in rats could be explained completely by poor oral absorption and hepatic first-pass metabolism; in monkeys, oral absorption was either less than in rats or first-pass extraction in the gut was greater. In an attempt to increase oral exposure, the pharmacokinetics and oral bioavailability of two potential prodrugs of 1, an N-ethyl [(R)-N-[4-[2-[ethyl[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide; 2] and a morpholine derivative [(R)-N-[4-[2-[2-(3-pyridinyl)morpholin-4-yl]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)- phenyl]thiazol-2-yl]benzenesulfonamide; 3], were evaluated in monkeys. Conversion to 1 was low (<3%) with both derivatives, and neither entity was an effective prodrug, but the oral bioavailability of 3 (56%) compared with 1 (4%) was significantly improved. The hypothesis that the increased oral bioavailability of 3 was due to a reduction in hydrogen bonding sites in the molecule led to the design of (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-2-yl)ethyl]amino]ethyl]phenyl]-4-[4-(4-trifluoromethylphenyl)thiazol-2-yl]benzenesulfonamide (4), a 2-pyridyl ₃-adrenergic receptor agonist with improved oral bioavailability in rats and monkeys.