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

• Published in: Journal of medicinal chemistry 2006-12, Vol.49 (25), p.7450-7465
• Main Authors: Patel, Meena V, Kolasa, Teodozyj, Mortell, Kathleen, Matulenko, Mark A, Hakeem, Ahmed A, Rohde, Jeffrey J, Nelson, Sherry L, Cowart, Marlon D, Nakane, Masaki, Miller, Loan N, Uchic, Marie E, Terranova, Marc A, El-Kouhen, Odile F, Donnelly-Roberts, Diana L, Namovic, Marian T, Hollingsworth, Peter R, Chang, Renjie, Martino, Brenda R, Wetter, Jill M, Marsh, Kennan C, Martin, Ruth, Darbyshire, John F, Gintant, Gary, Hsieh, Gin C, Moreland, Robert B, Sullivan, James P, Brioni, Jorge D, Stewart, Andrew O
• Format: Article
• Language: English
• Subjects: Action Potentials; Administration, Oral; Animals; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Biological and medical sciences; Biological Availability; Catecholaminergic system; Cell Line; Cyclic N-Oxides - chemical synthesis; Cyclic N-Oxides - chemistry; Cyclic N-Oxides - pharmacology; Dogs; Erectile Dysfunction - drug therapy; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - physiology; Genital system. Reproduction; Haplorhini; Humans; In Vitro Techniques; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Patch-Clamp Techniques; Pharmacology. Drug treatments; Purkinje Fibers - drug effects; Purkinje Fibers - physiology; Rats; Receptors, Dopamine D4 - agonists; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060662k

The goal of this study was to identify a structurally distinct D4-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.