Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzam ide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.

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Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO

Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzam ide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.

J Med Chem. 2006 Dec 14;49(25):7450-65.

PubMed ID
17149874 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ApomorphineDopamine D2 receptorEC 50 (nM)5.8N/AN/ADetails
ApomorphineDopamine D2 receptorKi (nM)3.6N/AN/ADetails
ApomorphineDopamine D2 receptorEC 50 (nM)1.8N/AN/ADetails
ApomorphineDopamine D4 receptorEC 50 (nM)4.3N/AN/ADetails
ApomorphineDopamine D4 receptorKi (nM)8.9N/AN/ADetails
ApomorphineDopamine D4 receptorEC 50 (nM)1.5N/AN/ADetails
DopamineDopamine D2 receptorEC 50 (nM)18N/AN/ADetails
DopamineDopamine D2 receptorEC 50 (nM)8N/AN/ADetails
DopamineDopamine D4 receptorEC 50 (nM)2.2N/AN/ADetails
DopamineDopamine D4 receptorEC 50 (nM)2.7N/AN/ADetails