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 Er

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• 作者：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. Terr
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 14, 2006
• 年：2006
• 卷：49
• 期：25
• 页码：7450 - 7465
• 全文大小：239K
• 年卷期：v.49,no.25(December 14, 2006)
• ISSN：1520-4804

文摘

The goal of this study was to identify a structurally distinct D₄-selective agonist with superior oralbioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectiledysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides suchas 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidinetemplate provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oralbioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discoveryof 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-pyridinylmoiety not only provided the structural motif required for agonist function but also reduced metabolismrates. The SAR study leading to the discovery of 6b is described herein.