Synthesis and pharmacological evaluation of aminopyrimidine series of 5-HT1A partial agonists

Aminopyrimidine 2 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine) emerged from a high throughput screen as a novel 5-HT(1A) agonist. This compound showed moderate potency for 5-HT(1A) in binding and functional assays, as well as moderate metabolic stability. Implementat...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-02, Vol.19 (4), p.1159-1163
Main Authors: Dounay, Amy B, Barta, Nancy S, Bikker, Jack A, Borosky, Susan A, Campbell, Brian M, Crawford, Terry, Denny, Lynne, Evans, Lori M, Gray, David L, Lee, Pil, Lenoir, Edward A, Xu, Wenjian
Format: Article
Language:English
Subjects:
Buspirone - pharmacology
Combinatorial Chemistry Techniques
Drug Design
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Molecular Structure
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Receptor, Serotonin, 5-HT1A - drug effects
Serotonin Receptor Agonists - chemical synthesis
Serotonin Receptor Agonists - chemistry
Serotonin Receptor Agonists - pharmacology
Structure-Activity Relationship
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Summary:Aminopyrimidine 2 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine) emerged from a high throughput screen as a novel 5-HT(1A) agonist. This compound showed moderate potency for 5-HT(1A) in binding and functional assays, as well as moderate metabolic stability. Implementation of a strategy for improving metabolic stability by lowering the lipophilicity (cLogD) led to identification of methyl ether 31 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine) as a substantially improved compound within the series.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2008.12.087