Author/Authors :
Tomoaki Komai، نويسنده , , Susumu Higashida، نويسنده , , Mitsuya Sakurai، نويسنده , , Tamayo Nitta، نويسنده , , Atsushi Kasuya، نويسنده , , Shuichi Miyamaoto، نويسنده , , Ryuichi Yagi، نويسنده , , Yuji Ozawa، نويسنده , , Hiroshi Handa، نويسنده , , Hiroshi Mohri، نويسنده , , Akira Yasuoka، نويسنده , , Shinichi Oka، نويسنده , , Takashi Nishigaki، نويسنده , , Satoshi Kimura، نويسنده , , Kaoru Shimada، نويسنده , , Yuichiro Yabe، نويسنده ,
Abstract :
Systematic replacement in the 3- or 4-position of the pyrrolidine ring at P1′ proline was carried out. Compound 26, which has a Cl atom in the 4(S)-position was the most active among inhibitors substituted with other halogen atoms or other substituents. Furthermore, the replacement of the Z group in compound 26 with five- or six-membered fused aromatic heterocycle carbonyl groups produced more potent inhibitors. 7-Methoxybenzofuran-2-carbonyl derivative (44) was the best of these and showed Ki = 4.5 nM against HIV PR and IC90s 0.58 μM and 0.06 μM in chronic and acute infections, respectively. These results suggest that the combination of the 4(S)-Cl atom and fused bicyclic heterocycles may be effective in improving their cellular penetration.
