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 β3-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 of3H-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 β3-adrenergic receptor agonist with improved oral bioavailability in rats and monkeys.
Footnotes
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↵2 Subsequently, the disposition of 1and 4 were evaluated in brain and plasma after i.v. dosing in CF1 mdr1a +/+ and −/− mice (data not shown). Plasma concentrations of both drugs were similar in each strain of mice, but the concentrations in brain were 5- to 7-fold higher in the −/− strain. This data suggested that both 1 and 4 were P-glycoprotein substrates and that the increased oral absorption of4 was not due to a difference in P-glycoprotein substrate selectivity but rather to an improvement in the intrinsic membrane permeability of this analogue.
- Abbreviations used are::
- 1
- (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethylphenyl]thiazol-2-yl]benzenesulfonamide
- 2
- (R)-N-[4-[2-[ethyl[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide
- 3
- (R)-N-[4-[2-[2-(3-pyridinyl)morpholin-4-yl]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide
- 4
- (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-2-yl)ethyl]amino]ethyl]phenyl]-4-[4-(4-trifluoromethylphenyl)thiazol-2-yl]benzenesulfonamide
- 5, (R)-4-[5-(3,4-difluorophenylmethyl)-1,2,4-oxadiazol-3-yl]-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino] ethyl]phenyl]benzenesulfonamide
- HPLC, high pressure liquid chromatography
- TFA
- trifluoroacetic acid
- PEG 400
- polyethylene glycol 400
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- AUC
- area under the plasma concentration-time curve
- Clp
- plasma clearance
- Vdss
- volume of distribution at steady state
- Received November 2, 2001.
- Accepted March 18, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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