abt-670

Description: ABT-670 is a novel, potent, selective, orally bioavailable agonist of dopamine D4 receptor with EC50 of 89 nM, 160 nM, and 93 nM for human?D4, ferret?D4, and rat?D4, respectively. It was discovered from a study aiming to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to the 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.

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