New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development.
On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,8 aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.
Research Laboratories Cancer and Infectious Diseases, Ciba-Geigy AG, CH-4002 Basel, Switzerland.
G
G
Bold
A
A
Fässler
H G
HG
Capraro
R
R
Cozens
T
T
Klimkait
J
J
Lazdins
J
J
Mestan
B
B
Poncioni
J
J
Rösel
D
D
Stover
M
M
Tintelnot-Blomley
F
F
Acemoglu
W
W
Beck
E
E
Boss
M
M
Eschbach
T
T
Hürlimann
E
E
Masso
S
S
Roussel
K
K
Ucci-Stoll
D
D
Wyss
M
M
Lang
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D001372:Aza Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D001682:Biological Availability; D004151:Dipeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D005260:Female; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D019469:Indinavir / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019258:Saquinavir / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D001372:Aza Compounds; D004151:Dipeptides; D017320:HIV Protease Inhibitors; D019469:Indinavir; D016333:HIV Protease; D019258:Saquinavir