Swain C J, Seward E M, Cascieri M A, Fong T M, Herbert R, MacIntyre D E, Merchant K J, Owen S N, Owens A P, Sabin V
Department of Medicinal Chemistry, Merck, Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
J Med Chem. 1995 Nov 24;38(24):4793-805. doi: 10.1021/jm00024a007.
The synthesis and in vitro and in vivo evaluation of a series of 3-(benzyloxy)-1-azabicyclo-[2.2.2]octane NK1 antagonists are described. While a number of 3,5-disubstituted benzyl ethers afford high affinity, the 3,5-bis(trifluoromethyl)benzyl was found to combine high in vitro affinity with good oral activity. Detailed structure-activity relationship studies in conjunction with data from molecular modeling and mutagenesis work have allowed the construction of a model of the pharmacophore. Specific interactions that have been identified include an interaction between His-197 and one of the rings of the benzhydryl, a lipophilic pocket containing His-265 that the benzyl ether occupies, and a possible hydrogen bond between Gln-165 and the oxygen of the benzyl ether.
描述了一系列3-(苄氧基)-1-氮杂双环[2.2.2]辛烷NK1拮抗剂的合成及其体外和体内评价。虽然许多3,5-二取代苄醚具有高亲和力，但发现3,5-双(三氟甲基)苄基兼具高体外亲和力和良好的口服活性。结合分子建模和诱变研究的数据进行的详细构效关系研究，使得能够构建药效团模型。已确定的特定相互作用包括His-197与二苯甲基的一个环之间的相互作用、苄醚占据的含有His-265的亲脂性口袋，以及Gln-165与苄醚的氧之间可能存在的氢键。
