Publications (2)10.41 Total impact
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Article: Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
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ABSTRACT: The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.Journal of Medicinal Chemistry 01/2007; 49(25):7450-65. · 5.25 Impact Factor -
Article: Mesoridazine: an open-channel blocker of human ether-a-go-go-related gene K+ channel.
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ABSTRACT: Mesoridazine, a phenothiazine antipsychotic agent, prolongs the QT interval of the cardiac electrocardiogram and is associated with Torsade de pointes-type arrhythmias. In this study, we examined the effects of mesoridazine on human ether-a-go-go-related gene (HERG) K+ currents. HERG channels were stably expressed in human embryonic kidney 293 cells and studied using standard whole-cell patch-clamp technique (37 degrees C). Mesoridazine blocked HERG currents in a concentration-dependent manner (IC50 550 nM at 0 mV); block increased significantly over the voltage range where HERG activates and saturated at voltages eliciting maximal HERG channel activation. Tonic block of HERG current by mesoridazine (1.8 microM) was minimal (< 2-4%). The rate of the onset of HERG channel block was rapid and dose dependent (tau = 54 +/- 7 ms at 0 mV and 1.8 microM mesoridazine), but not significantly affected by test potentials ranging from -30 to +30 mV. The V1/2 for steady-state activation was shifted from -31.2 +/- 1.0 to -39.2 +/- 0.5 mV (P < 0.01). The apparent rate of HERG channel deactivation was significantly reduced (fast tau = 153 +/- 8 vs. 102 +/- 6 ms at -50 mV, P < 0.01; slow tau = 1113 +/- 63 vs. 508 +/- 27 ms, P < 0.01). The inactivation kinetics and voltage dependence of steady-state inactivation of the HERG channel were not significantly altered by mesoridazine. These findings demonstrate that mesoridazine is a potent and rapid open-channel blocker of HERG channels. This block would explain the QT prolongation seen clinically at therapeutic concentrations (0.3-3.6 microM).Journal of Molecular and Cellular Cardiology 01/2004; 36(1):151-60. · 5.17 Impact Factor
