The synthesis of symmetrical and unsymmetrical P1/P1' cyclic ureas as HIV protease inhibitors.
Cyclic urea SD146, a potent HIV protease inhibitor bearing a flat resistance profile, possessed poor solubility and bioavailability, which precluded further development of the compound. In an effort to improve upon the pharmacokinetic profile of the compound, several analogs modified at the P1/P1' residues were prepared and evaluated. Several of those compounds displayed significant improvement of physical properties.
Patel
M
M
Department of Chemical & Physical Sciences, DuPont Merck Pharmaceutical Company, Wilmington, DE 19880-0500, USA.
Kaltenbach
R F
RF
Nugiel
D A
DA
McHugh
R J
RJ
Jadhav
P K
PK
Bacheler
L T
LT
Cordova
B C
BC
Klabe
R M
RM
Erickson-Viitanen
S
S
Garber
S
S
Reid
C
C
Seitz
S P
SP
D001665:Binding Sites; D001682:Biological Availability; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D017320:HIV Protease Inhibitors; C112386:SD 146 cyclic urea; D014508:Urea; D016333:HIV Protease