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Synthesis and structure-activity relationships of novel histamine H1 antagonists: indolylpiperidinyl benzoic acid derivatives
Authors:Fonquerna Silvia  Miralpeix Montse  Pagès Lluís  Puig Carles  Cardús Arantxa  Antón Francisca  Cárdenas Alvaro  Vilella Dolors  Aparici Mónica  Calaf Elena  Prieto José  Gras Jordi  Huerta Josep M  Warrellow Graham  Beleta Jorge  Ryder Hamish
Affiliation:Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024-Barcelona, Spain. sfonquerna@almirall.es
Abstract:
A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
Keywords:
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