Discovery of 2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a Dopaminergic Agent with a Novel Mode of Action for the Potential Treatment of Erectile Dysfunction

• Published in: Journal of medicinal chemistry Vol. 47; no. 15; pp. 3853 - 3864
• Main Authors: Cowart, Marlon, Latshaw, Steven P, Bhatia, Pramila, Daanen, Jerome F, Rohde, Jeffrey, Nelson, Sherry L, Patel, Meena, Kolasa, Teodozyi, Nakane, Masaki, Uchic, Marie E, Miller, Loan N, Terranova, Marc A, Chang, Renjie, Donnelly-Roberts, Diana L, Namovic, Marian T, Hollingsworth, Peter R, Martino, Brenda R, Lynch, James J, Sullivan, James P, Hsieh, Gin C, Moreland, Robert B, Brioni, Jorge D, Stewart, Andrew O
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 15-07-2004
• Subjects: Animals; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Benzimidazoles - toxicity; Biological and medical sciences; Cell Line; Erectile Dysfunction - drug therapy; Ferrets; Genital system. Reproduction; Humans; Male; Medical sciences; Penile Erection - drug effects; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Piperazines - toxicity; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyridines - toxicity; Radioligand Assay; Rats; Rats, Wistar; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D4; Structure-Activity Relationship; Vomiting - chemically induced; Agonist; Rat; Nitrogen heterocycle; Selectivity; Pyridine derivatives; Structure activity relation; Bicyclic compound; Subcutaneous administration; Aromatic compound; Chemical synthesis; Male genital diseases; Human; D4 Dopamine receptor; Erection disorders; Rodentia; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; Dopamine agonist; Affinity; Piperazine derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030505a

A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 μmol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure−activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.