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
Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024-Barcelona, Spain.
J Med Chem. 2004 Dec 2;47(25):6326-37. doi: 10.1021/jm0498203.
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.
制备了一系列吲哚基哌啶基衍生物，并对其作为组胺H(1)拮抗剂的活性进行了评估。构效关系研究旨在改善我们的首个先导化合物(1)的体内活性和药代动力学特征。在吲哚环的6位上取代氟导致在组胺诱导的皮肤血管通透性测定中具有更高的体内活性，但对5HT(2)受体的选择性较低。在该系列中进行了广泛的优化，鉴定出了一些在体内显示出效力和长效作用且脑渗透性低或心脏毒性潜力低的组胺H(1)拮抗剂。在这个新系列中，吲哚基哌啶15、20、48、51和52在大鼠中表现出长半衰期，并已被选作进一步的临床前评估。
