Publication Date:
1994-01-21
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lam, P Y -- Jadhav, P K -- Eyermann, C J -- Hodge, C N -- Ru, Y -- Bacheler, L T -- Meek, J L -- Otto, M J -- Rayner, M M -- Wong, Y N -- New York, N.Y. -- Science. 1994 Jan 21;263(5145):380-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Virology Research, DuPont Merck Pharmaceutical Company, Wilmington, DE 19880.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8278812" target="_blank"〉PubMed〈/a〉
Keywords:
Administration, Oral
;
Animals
;
Azepines/*chemistry/metabolism/pharmacokinetics/pharmacology
;
Binding Sites
;
Biological Availability
;
Cell Line
;
Crystallography, X-Ray
;
Dogs
;
*Drug Design
;
Drug Evaluation, Preclinical
;
HIV Protease/chemistry/metabolism
;
HIV Protease Inhibitors/*chemistry/metabolism/pharmacokinetics/pharmacology
;
HIV-1/drug effects/physiology
;
Hydrogen Bonding
;
Models, Molecular
;
Molecular Conformation
;
Molecular Weight
;
Rats
;
Recombinant Proteins/chemistry/metabolism
;
Urea
;
Virus Replication/drug effects
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink