Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands.
A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.
Ghosh
A K
AK
Department of Medicinal Chemistry, Merck Research Laboratory, West Point, Pennsylvania 19486.
Thompson
W J
WJ
Holloway
M K
MK
McKee
S P
SP
Duong
T T
TT
Lee
H Y
HY
Munson
P M
PM
Smith
A M
AM
Wai
J M
JM
Darke
P L
PL
D000998:Antiviral Agents / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors