Discovery and optimization of nonpeptide HIV-1 protease inhibitors.
Several small, achiral nonpeptide inhibitors of HIV-1 protease with low micromolar activity were identified by mass screening of the Parke-Davis compound library. Two of the compounds, structurally similar, were both found to be competitive and reversible inhibitors [compound 1, 4-hydroxy-3-(3-phenoxypropyl)-1-benzopyran-2-one: Ki = 1.0 microM; compound 2, 4-hydroxy-6-phenyl-3-(phenylthio)-pyran-2-one: Ki = 1.1 microM]. These inhibitors were chosen as initial leads for optimization of in vitro inhibitory activity based on molecular modeling and X-ray crystallographic structural data. While improvements in inhibitory potency were small with analogues of compound 1, important X-ray crystallographic structural information of the enzyme-inhibitor complex was gained. When bound, 1 was found to displace H2O301 in the active site while hydrogen bonding to the catalytic Asps and Ile50 and Ile150. The pyranone group of compound 2 was found to bind at the active site in the same manner, with the 6-phenyl and the 3-phenylthio occupying P1 and P1', respectively. The structural information was used to develop design strategies to reach three or four of the internal pockets, P2-P2'. This work led to analogues of diverse structure with high potency (IC50 < 10 nM) that contain either one or no chiral centers and remain nonpeptide. The highly potent compounds possess less anti-HIV activity in cellular assays than expected, and current optimization now focuses on increasing cellular activity. The value of the HIV-1 protease inhibitors described is their potential as better pharmacological agents with a different pattern of viral resistance development, relative to the peptide inhibitors in human clinical trials.
Department of Biochemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
P J
PJ
Tummino
J V
JV
Prasad
D
D
Ferguson
C
C
Nouhan
N
N
Graham
J M
JM
Domagala
E
E
Ellsworth
C
C
Gajda
S E
SE
Hagen
E A
EA
Lunney
K S
KS
Para
B D
BD
Tait
A
A
Pavlovsky
J W
JW
Erickson
S
S
Gracheck
T J
TJ
McQuade
D J
DJ
Hupe
D001578:Benzopyrans / Q000737:chemistry; D055598:Chemical Phenomena; D002621:Chemistry; D018360:Crystallography, X-Ray; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular
D001578:Benzopyrans; D017320:HIV Protease Inhibitors