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  • Title: 4-(Phenylsulfonyl)piperidines: novel, selective, and bioavailable 5-HT(2A) receptor antagonists.
    Author: Fletcher SR, Burkamp F, Blurton P, Cheng SK, Clarkson R, O'Connor D, Spinks D, Tudge M, van Niel MB, Patel S, Chapman K, Marwood R, Shepheard S, Bentley G, Cook GP, Bristow LJ, Castro JL, Hutson PH, MacLeod AM.
    Journal: J Med Chem; 2002 Jan 17; 45(2):492-503. PubMed ID: 11784153.
    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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