The Pharmacokinetics of a Thiazole Benzenesulfonamide β₃-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability

Abstract

ABSTRACT:The pharmacokinetics and oral bioavailability of (R)-N- [4-[2-[[2-hydroxy-2-(pyridin-3-yl) [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 (ϳ30 ml/min/kg) than in dogs and monkeys (both ϳ10 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 3 H-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- 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 (Ͻ3%) 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) The prevalence of obesity is increasing throughout the world and especially in the United States (Kuczmarski et al., 1994, Wickelgren, 1998. This health risk is associated with the onset of other conditions such as noninsulin-dependent diabetes and cardiovascular disease (Pi-Sunyer, 1993). Basically, obesity is the result of an imbalance between caloric intake and energy expenditure. The challenge of reducing caloric intake in an obese population has led to a focus on pharmaceutical intervention to achieve weight loss. A number of therapeutic strategies have been explored for the pharmacological treatment of obesity (Kordik and Reitz, 1999). One potential mechanism for increasing energy expenditure is via activation of a unique ␤-adrenergic receptor subtype, the ␤ 3 -adrenergic receptor (Arch and Wilson, 1996;Dow, 1997;Weber, 1998). This receptor has been identified on the surface of rat adipocytes, and its activation results in the stimulation of lipolysis (Arch et al., 1984). In brown adipose tissue, ␤ 3 -adrenergic receptor activation leads to up-regulation of UCP1, a mitochondria...

Metabolism of a Thiazole Benzenesulfonamide Derivative, a Potent and Selective Agonist of the Human β3-Adrenergic Receptor, in Rats: Identification of a Novel Isethionic Acid Conjugate

“…The systemic clearance of 1 in experimental animal species is moderate and can be accounted for mainly by hepatic extraction (Stearns et al, 2002). When rats were treated with 3 H-labeled 1, most of the radiolabeled components were found in the bile with biliary radiochromatographic profiles being similar following either oral or intravenous administration.…”

“…3 H-labeled 1 at 10 mg/kg, 22% of the administered radioactivity was found in the bile, 6% in the urine, and 75% in the feces (Stearns et al, 2002). After intravenous dosing at 3 mg/kg, 63% of the radioactivity was recovered in the bile, 11% in the urine, and 9% in the feces (Stearns et al, 2002).…”

“…Anilino-2-3 H-labeled 1 and 1 hydrochloride were synthesized at Merck Research Laboratories (Mathvink et al, 2000;Stearns et al, 2002). The specific activity of 3 H-labeled 1 was 1750 mCi/mmol with a radiochemical purity greater than 97%.…”

“…After intravenous dosing at 3 mg/kg, 63% of the radioactivity was recovered in the bile, 11% in the urine, and 9% in the feces (Stearns et al, 2002). Bile, urine, and the homogenate of feces were further analyzed by HPLC and LC/MS/MS.…”

“…In addition, (R)-N- [4-[2-[[2-hydroxy-2-(pyridin-3-yl) Fig. 1), a nanomolar ag-onist of the human ␤ 3 -adrenergic receptor with a 1000-fold selectivity over ␤ 1 and ␤ 2 receptors, has been reported (Mathvink et al, 2000), and its pharmacokinetic characteristics described in the preceding article (Stearns et al, 2002). We report herein the results derived from studies of the biotransformation and excretion of 1 in bile ductcannulated rats.…”