Discovery of novel benzothiazolesulfonamides as potent inhibitors of HIV-1 protease.
The human immunodeficiency virus (HIV) has been shown to be the causative agent for AIDS. The HIV virus encodes for a unique aspartyl protease that is essential for the production of enzymes and proteins in the final stages of maturation. Protease inhibitors have been useful in combating the disease. The inhibitors incorporate a variety of isosteres including the hydroxyethylurea at the protease cleavage site. We have shown that the replacement of t-butylurea moiety by benzothiazolesulfonamide provided inhibitors with improved potency and antiviral activities. Some of the compounds have shown good oral bioavailability and half-life in rats. The synthesis of benzothiazole derivatives led us to explore other heterocycles. During the course of our studies, we also developed an efficient synthesis of benzothiazole-6-sulfonic acid via a two-step procedure starting from sulfanilamide.
Nagarajan
Srinivasan R
SR
Pfizer Global Research and Development, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. srinivasan.nagarajan@pfizer.com
De Crescenzo
Gary A
GA
Getman
Daniel P
DP
Lu
Hwang Fun
HF
Sikorski
James A
JA
Walker
Jeffrey L
JL
McDonald
Joseph J
JJ
Houseman
Kathryn A
KA
Kocan
Geralyn P
GP
Kishore
Nandini
N
Mehta
Pramod P
PP
Funkes-Shippy
Christie L
CL
Blystone
Lisa
L
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; D014508:Urea; C006865:butylurea; D016333:HIV Protease