Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors.
Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.
Lam
P Y
PY
Department of Virology Research, DuPont Merck Pharmaceutical Company, Wilmington, DE 19880.
Jadhav
P K
PK
Eyermann
C J
CJ
Hodge
C N
CN
Ru
Y
Y
Bacheler
L T
LT
Meek
J L
JL
Otto
M J
MJ
Rayner
M M
MM
Wong
Y N
YN
D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014508:Urea; D014779:Virus Replication / Q000187:drug effects
D001381:Azepines; D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins; D014508:Urea; D016333:HIV Protease