Aza-peptide analogs as potent human immunodeficiency virus type-1 protease inhibitors with oral bioavailability.
A series of aza-peptide analogs with a (hydroxyethyl)hydrazine isostere has been synthesized as HIV-1 protease inhibitors using a simple synthetic scheme. Structure-activity studies based on the X-ray of a previously described inhibitor-enzyme complex led to potent inhibitors with antiviral activity in the low-nanomolar range. The S-configuration of the transition-state hydroxyl group was preferred in this series. Small modifications of the P2P3 and P2'P3' substituents had little effect on enzyme inhibition but greatly influenced the pharmacokinetic profile. As a result of these studies, the symmetrically acylated compound 8a and its close analog 24a bearing a methyl carbamate in P3 and an ethyl carbamate in P3' position were identified as potent inhibitors with plasma concentrations exceeding antiviral ED50 values 150-fold following oral application in mice.
Fässler
A
A
Research Laboratories Cancer and Infectious Diseases, Ciba-Geigy AG, Basel, Switzerland.
Bold
G
G
Capraro
H G
HG
Cozens
R
R
Mestan
J
J
Poncioni
B
B
Rösel
J
J
Tintelnot-Blomley
M
M
Lang
M
M
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002478:Cells, Cultured; D005260:Female; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006834:Hydrazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D006834:Hydrazines; D016333:HIV Protease