The synthesis and biological evaluation of quinolyl-piperazinyl piperidines as potent serotonin 5-HT1A antagonists

J Med Chem. 2010 May 27;53(10):4066-84. doi: 10.1021/jm1000908.

Wayne E Childers Jr ¹, Lisa M Havran, Magda Asselin, James J Bicksler, Dan C Chong, George T Grosu, Zhongqi Shen, Magid A Abou-Gharbia, Alvin C Bach 3rd, Boyd L Harrison, Natasha Kagan, Teresa Kleintop, Ronald Magolda, Vasilios Marathias, Albert J Robichaud, Annmarie L Sabb, Mei-Yi Zhang, Terrance H Andree, Susan H Aschmies, Chad Beyer, Thomas A Comery, Mark Day, Steven M Grauer, Zoe A Hughes, Sharon Rosenzweig-Lipson, Brian Platt, Claudine Pulicicchio, Deborah E Smith, Stacy J Sukoff-Rizzo, Kelly M Sullivan, Adedayo Adedoyin, Christine Huselton, Warren D Hirst

Affiliations

Affiliation

1 Chemical Sciences, Pfizer Global Research and Development, Princeton, New Jersey 08543-8000, USA. [email protected]

PMID: 20443629 DOI: 10.1021/jm1000908

Abstract

As part of an effort to identify 5-HT(1A) antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT(1A) antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT(1A) antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.

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