Potent human immunodeficiency virus type 1 protease inhibitors that utilize noncoded D-amino acids as P2/P3 ligands.
Noncoded D-amino acids have been designed to replace the quinaldic amide-asparaginyl moiety (P2/P3 ligand) found in several potent human immunodeficiency virus (HIV) protease inhibitors such as LY289612. The substituted nitrogen, optimally an N-methanesulfonyl moiety, served as a CH2CONH2 (asparagine side chain mimic), while the amino acid side chain became the backbone and P3 ligand of these novel inhibitors. Compounds derived from S-aryl-D-cysteine proved to be potent HIV protease inhibitors which also exhibited potent whole cell antiviral activity. Oxidation of the cysteines to the sulfoxide or sulfone oxidation states resulted in significant improvements in potency. For example, the compound derived from N-(methyl-sulfonyl)-2-S-naphthylcysteine sulfone, 17c, was a 3.5 nM inhibitor of HIV protease which inhibited the spread of virus in MT4 cells with an IC50 = 4.3 nM. Compounds 17c,g,i were found to be orally bioavailable in a rat model.
Jungheim
L N
LN
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285-1523, USA.
Shepherd
T A
TA
Baxter
A J
AJ
Burgess
J
J
Hatch
S D
SD
Lubbehusen
P
P
Wiskerchen
M
M
Muesing
M A
MA
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001682:Biological Availability; D003545:Cysteine / Q000031:analogs & derivatives*; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology
D000596:Amino Acids; D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D008024:Ligands; D013450:Sulfones; D016333:HIV Protease; D003545:Cysteine