Structure-activity relationships of HIV-1 PR inhibitors containing AHPBA--II. Modification of pyrrolidine ring at P1' proline.
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 microM and 0.06 microM in chronic and acute infections, respectively. These results suggest that the combination of the 4(S)-CI atom and fused bicyclic heterocycles may be effective in improving their cellular penetration.
Komai
T
T
Biological Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan.
Higashida
S
S
Sakurai
M
M
Nitta
T
T
Kasuya
A
A
Miyamaoto
S
S
Yagi
R
R
Ozawa
Y
Y
Handa
H
H
Mohri
H
H
Yasuoka
A
A
Oka
S
S
Nishigaki
T
T
Kimura
S
S
Shimada
K
K
Yabe
Y
Y
D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D010654:Phenylbutyrates / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; D011759:Pyrrolidines; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid