Publications (4)13.07 Total impact
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Article: Pharmacokinetics, safety, and tolerability of phentermine in healthy participants receiving taranabant, a novel cannabinoid-1 receptor (CB1R) inverse agonist.
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ABSTRACT: This study assessed the potential pharmacokinetic interaction and safety/tolerability of taranabant and phentermine coadministration. This was a randomized, double-blind, 3-panel, fixed-sequence study in healthy participants. Panels A, B, and C evaluated the safety/tolerability of phentermine 15 mg coadministered with taranabant 0.5, 1, and 2 mg for 7 days (panel A) and 28 days (panels B and C). In panels A and C, phentermine 15 mg was administered both with (7 days, panel A; 28 days, panel C) and without (7 days) taranabant 0.5 mg or 2 mg to evaluate pharmacokinetics. The primary endpoint was phentermine AUC(0-24 h) in panels A and C. Secondary endpoints were changes from baseline in blood pressure and heart rate for all panels. The geometric mean ratios and 90% confidence intervals for phentermine AUC(0-24 h) in the presence/absence of taranabant 0.5 mg and 2 mg were 1.08 (0.99, 1.17) and 1.04 (0.98, 1.10), respectively. No significant differences in blood pressure and heart rate were observed with any treatment versus placebo. Coadministration of taranabant 0.5 mg, 1 mg, and 2 mg with phentermine was well tolerated with no pharmacokinetic interaction and did not result in meaningful changes in blood pressure or heart rate versus placebo.The Journal of Clinical Pharmacology 10/2009; 49(10):1228-38. · 2.91 Impact Factor -
Article: Effects of laropiprant, a selective prostaglandin D(2) receptor 1 antagonist, on the pharmacokinetics of rosiglitazone.
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ABSTRACT: Laropiprant (LRPT), a prostaglandin D(2) receptor-1 antagonist shown to reduce niacin-induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, randomized, 2-period crossover study assessed the pharmacokinetics of single-dose rosiglitazone in the presence and absence of multiple-dose LRPT. Twelve healthy male and female subjects, 34-64 years of age, received two, once-daily oral treatments in random sequence separated by >/=3-day washout: (1) multiple-dose LRPT 40 mg/day for 7 days (Days 1 to 7) coadministered with single-dose rosiglitazone 4 mg on Day 6; (2) single-dose rosiglitazone 4 mg on Day 1. Comparability was declared because the 90% confidence interval (CI) for the AUC(0-infinity) geometric mean ratio (GMR; rosiglitazone + LRPT/rosiglitazone alone) [0.92 (0.86, 0.99)], was contained within prespecified bounds (0.70, 1.43). The C(max) GMR (90% CI) for rosiglitazone was 0.98 (0.95, 1.02). There was no evidence of clinically meaningful alterations in the pharmacokinetics of rosiglitazone, a probe CYP2C8 substrate, following coadministration of multiple-dose LRPT in healthy subjects. Therefore, findings suggest that LRPT does not inhibit CYP2C8-mediated metabolism.Cardiovascular Therapeutics 01/2009; 27(4):239-45. · 2.35 Impact Factor -
Article: Substituted acyclic sulfonamides as human cannabinoid-1 receptor inverse agonists.
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ABSTRACT: Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia.Bioorganic & Medicinal Chemistry Letters 05/2007; 17(8):2184-7. · 2.55 Impact Factor -
Article: Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity.
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ABSTRACT: The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.Journal of Medicinal Chemistry 01/2007; 49(26):7584-7. · 5.25 Impact Factor
