Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1' phenyl substituents: X-ray crystal structure assisted design.
By tethering of a polar hydrophilic group to the P1 or P1' substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 A verifies the modeling predictions.
Thompson
W J
WJ
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
Fitzgerald
P M
PM
Holloway
M K
MK
Emini
E A
EA
Darke
P L
PL
McKeever
B M
BM
Schleif
W A
WA
Quintero
J C
JC
Zugay
J A
JA
Tucker
T J
TJ
D001665:Binding Sites; D002478:Cells, Cultured; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D014961:X-Ray Diffraction
D017320:HIV Protease Inhibitors; D009025:Morpholines; D010455:Peptides; D011480:Protease Inhibitors; C072111:L 689502; D016333:HIV Protease