title: The pharmacokinetics of a thiazole benzenesulfonamide beta 3-adrenergic receptor agonist and its analogs in rats, dogs, and monkeys: improving oral bioavailability.
abstract: 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 beta3-adrenergic receptor agonist, were investigated in rats, dogs, and monkeys. Systemic clearance was higher in rats (approximately 30 ml/min/kg) than in dogs and monkeys (both approximately 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 beta3-adrenergic receptor agonist with improved oral bioavailability in rats and monkeys.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey 07065, USA. ralph_stearns@merck.com
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Stearns
authors.forename: Randy R
authors.initials: RR
authors.lastname: Miller
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Gloria Y
authors.initials: GY
authors.lastname: Kwei
authors.forename: Frank S
authors.initials: FS
authors.lastname: Tang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mathvink
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Naylor
authors.forename: Dawn
authors.initials: D
authors.lastname: Chitty
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Colandrea
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
authors.forename: Adria E
authors.initials: AE
authors.lastname: Colletti
authors.forename: John R
authors.initials: JR
authors.lastname: Strauss
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Keohane
authors.forename: William P
authors.initials: WP
authors.lastname: Feeney
authors.forename: Susan A
authors.initials: SA
authors.lastname: Iliff
authors.forename: Shuet-Hing Lee
authors.initials: SH
authors.lastname: Chiu
mesh_terms: D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D000096926:Benzenesulfonamides
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; D013844:Thiazoles; D000096926:Benzenesulfonamides