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, 45 (2), 492-503

4-(Phenylsulfonyl)piperidines: Novel, Selective, and Bioavailable 5-HT(2A) Receptor Antagonists

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4-(Phenylsulfonyl)piperidines: Novel, Selective, and Bioavailable 5-HT(2A) Receptor Antagonists

Stephen R Fletcher et al. J Med Chem.

Abstract

On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.

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