Le Bourdonnec B, Meulon E, Yous S, Goossens J F, Houssin R, Hénichart J P
Institut de Chimie Pharmaceutique Albert Lespagnol and Laboratoire de Chimie Analytique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2, rue du Professeur Laguesse, BP 83, F-59006 Lille, France.
J Med Chem. 2000 Jul 13;43(14):2685-97. doi: 10.1021/jm9904147.
On the basis of the structure of the non-peptide receptor antagonist irbesartan, a new series of AT(1) ligands was designed. In these compounds the central imidazolone nucleus of irbesartan was replaced by a pyrazolidine-3,5-dione structure. The key intermediate N-alkylpyrazolidine-3,5-diones were synthesized according to a new and general method. The most active compounds possess a spirocyclopentane ring at position 4, a linear butyl chain at position 1, and the [2'-(5-tetrazolyl)biphenyl-4-yl]methyl or [2'-(benzoylaminosulfonyl)biphenyl-4-yl]methyl group at position 2. Affinity toward the AT(1) and AT(2) receptors was assessed by the ability of the compounds to competitively displace [(3)H]AII from its specific binding sites. The most active compounds, 28 and 48, displayed high affinity for the AT(1) receptor, good selectivity AT(1) versus AT(2), and potent in vitro antagonist activity.
基于非肽类受体拮抗剂厄贝沙坦的结构，设计了一系列新型的AT(1)配体。在这些化合物中，厄贝沙坦的中心咪唑啉酮核被吡唑烷-3,5-二酮结构所取代。关键中间体N-烷基吡唑烷-3,5-二酮是根据一种新的通用方法合成的。活性最高的化合物在4位具有螺环戊烷环，在1位具有直链丁基链，在2位具有[2'-(5-四唑基)联苯-4-基]甲基或[2'-(苯甲酰氨基磺酰基)联苯-4-基]甲基基团。通过化合物从其特异性结合位点竞争性置换[(3)H]AII的能力来评估对AT(1)和AT(2)受体的亲和力。活性最高的化合物28和48对AT(1)受体表现出高亲和力，对AT(1)与AT(2)具有良好的选择性，并且具有强大的体外拮抗剂活性。
