IDENTIFICATION OF A SERIES OF 3-(BENZYLOXY)-1-AZABICYCLO[2.2.2]OCTANEHUMAN NK1 ANTAGONISTS

The synthesis and in vitro and in vivo evaluation of a series of 3-(be nzyloxy)-1-azabicyclo[2.2.2]octane NK1 antagonists are described. Whil e a number of 3,5-disubstituted benzyl ethers afford high affinity, th e 3,5-bis(trifluoromethyl)benzyl was found to combine high in vitro af finity with good oral activity. Detailed structure-activity relationsh ip studies in conjunction with data from molecular modeling and mutage nesis work have allowed the construction of a model of the pharmacopho re. Specific interactions that have been identified include an interac tion between His-197 and one of the rings of the benzhydryl, a Lipophi lic pocket containing His-265 that the benzyl ether occupies, and a po ssible hydrogen bond between Gln-165 and the oxygen of the benzyl ethe r.