52321-77-4Relevant academic research and scientific papers
Identification of a series of 3-(benzyloxy)-1-azabicyclo[2.2.2]octane human NK1 antagonists
Swain,Seward,Cascieri,Fong,Herbert,MacIntyre,Merchant,Owen,Owens,Sabin,Teall,VanNiel,Williams,Sadowski,Strader,Ball,Baker
, p. 4793 - 4805 (2007/10/03)
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.
Quinuclidine chemistry. 2. Synthesis and antiinflammatory properties of 2 substituted benzhydryl 3 quinuclidinols
Warawa,Mueller,Jules
, p. 497 - 501 (2007/10/05)
A number of 2 benzhydryl 3 quinuclidinols were tested for their anti inflammatory activity. The cis isomers were prepared selectively by aluminum isopropoxide reduction of the ketones which were made by the addition of aromatic Grignard reagents to 2 benzylidene 3 quinuclidinones. The most active compound was cis 2 (4,4' difluorobenzhydryl) 3 quinuclidinol. The trans alcohol was less active than the cis isomer. It was made by selectively oxidizing the cis alcohol in a mixture of cis and trans alcohols (formed by NaBH4 reduction of the ketone) followed by chromatography. The two diastereoisomers of the monofluorinated alcohol, 2 (4 fluorobenzhydryl) 3 quinuclidinol, showed activity but were markedly less active than the difluorinated alcohol. The quinuclidine nitrogen was vital for activity for cis 3 (4,4 difluorobenzhydryl) bicyclo [2.2.2] octan 2 one showed only marginal activity.
