2-(3--4--5--6--tetrahydro-2-h-(2-4-)-bipyridinyl-1--yl)-n-m-tolyl-acetamide and Erectile-Dysfunction

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.

Topics: Action Potentials; Administration, Oral; Animals; Benzamides; Biological Availability; Cell Line; Cyclic N-Oxides; Dogs; Erectile Dysfunction; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Haplorhini; Humans; In Vitro Techniques; Male; Patch-Clamp Techniques; Purkinje Fibers; Rats; Receptors, Dopamine D4; Structure-Activity Relationship