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

  • J Med Chem. 2006 Dec 14;49(25):7450-65. doi: 10.1021/jm060662k.
Meena V Patel  1 ,  Teodozyj Kolasa ,  Kathleen Mortell ,  Mark A Matulenko ,  Ahmed A Hakeem ,  Jeffrey J Rohde ,  Sherry L Nelson ,  Marlon D Cowart ,  Masaki Nakane ,  Loan N Miller ,  Marie E Uchic ,  Marc A Terranova ,  Odile F El-Kouhen ,  Diana L Donnelly-Roberts ,  Marian T Namovic ,  Peter R Hollingsworth ,  Renjie Chang ,  Brenda R Martino ,  Jill M Wetter ,  Kennan C Marsh ,  Ruth Martin ,  John F Darbyshire ,  Gary Gintant ,  Gin C Hsieh ,  Robert B Moreland ,  James P Sullivan ,  Jorge D Brioni ,  Andrew O Stewart
Affiliations
  • 1. Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA. [email protected]
PMID: 17149874 DOI: 10.1021/jm060662k
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.

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