Aminodiol HIV protease inhibitors. Synthesis and structure-activity relationships of P1/P1' compounds: correlation between lipophilicity and cytotoxicity.
A series of novel aminodiol inhibitors of HIV protease based on the lead compound 1 with structural modifications at P1' were synthesized in order to reduce the cytotoxicity of 1. We have observed a high degree of correlation between the lipophilicity and cytotoxicity of this series of inhibitors. It was found that appropriate substitution at the para position of the P1' phenyl group of 1 resulted in the identification of equipotent (both against the enzyme and in cell culture) compounds (10l, 10m, 10n, and 15c) which possess significantly decreased cytotoxicity.
Chen
P
P
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Cheng
P T
PT
Alam
M
M
Beyer
B D
BD
Bisacchi
G S
GS
Dejneka
T
T
Evans
A J
AJ
Greytok
J A
JA
Hermsmeier
M A
MA
Humphreys
W G
WG
Jacobs
G A
GA
Kocy
O
O
Lin
P F
PF
Lis
K A
KA
Marella
M A
MA
Ryono
D E
DE
Sheaffer
A K
AK
Spergel
S H
SH
Sun
C Q
CQ
Tino
J A
JA
Vite
G
G
Colonno
R J
RJ
Zahler
R
R
Barrish
J C
JC
D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship
D000588:Amines; D017320:HIV Protease Inhibitors