Document Detail


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.
MedLine Citation:
PMID:  17149874     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Meena V Patel; 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
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-12-07     Completed Date:  2007-02-23     Revised Date:  2008-10-28    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7450-65     Citation Subset:  IM    
Affiliation:
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA. meena.v.patel@abbott.com
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MeSH Terms
Descriptor/Qualifier:
Action Potentials
Administration, Oral
Animals
Benzamides / chemical synthesis*,  chemistry,  pharmacology
Biological Availability
Cell Line
Cyclic N-Oxides / chemical synthesis*,  chemistry,  pharmacology
Dogs
Erectile Dysfunction / drug therapy*
Ether-A-Go-Go Potassium Channels / physiology
Haplorhini
Humans
Male
Patch-Clamp Techniques
Purkinje Fibers / drug effects,  physiology
Rats
Receptors, Dopamine D4 / agonists*
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-(2,4'-bipyridine)-1'-ylmethyl)benzamide; 0/Benzamides; 0/Cyclic N-Oxides; 0/ERG1 potassium channel; 0/Ether-A-Go-Go Potassium Channels; 137750-34-6/Receptors, Dopamine D4

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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