An Orally Bioavailable Pyrrolinone Inhibitor of HIV-1 Protease: Computational Analysis and X-ray Crystal Structure of the Enzyme Complex

We have described several potent inhibitors of the HIV-1 protease, based on the novel 3,5-linked bispyrrolinone scaffold which we developed to mimic the peptidal beta -strand/ beta -sheet structural motif. Our most active bispyrrolinone (IC sub(50) 1.3 nM, CIC sub(95) 800 nM) was not orally bioavail...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 40; no. 16; pp. 2440 - 2444
Main Authors:	Smith, Amos B, Hirschmann, Ralph, Pasternak, Alexander, Yao, Wenquing, Sprengeler, Paul A, Holloway, M. Katharine, Kuo, Lawrence C, Chen, Zhongguo, Darke, Paul L, Schleif, William A
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-08-1997
Subjects:	Administration, Oral AIDS/HIV Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - administration & dosage Antiviral Agents - chemistry Antiviral Agents - pharmacokinetics Biological and medical sciences Biological Availability Crystallography, X-Ray Dipeptides - administration & dosage Dipeptides - chemistry Dipeptides - pharmacokinetics Drug Design HIV Protease - metabolism HIV Protease Inhibitors - administration & dosage HIV Protease Inhibitors - chemistry HIV Protease Inhibitors - pharmacokinetics human immunodeficiency virus 1 Hydrogen Bonding Indinavir - chemistry Indoles - administration & dosage Indoles - chemistry Indoles - pharmacokinetics Medical sciences Models, Molecular Molecular Weight Pharmacology. Drug treatments Protein Conformation Pyrroles - administration & dosage Pyrroles - chemistry Pyrroles - pharmacokinetics Aminoalcohol Indan derivatives HIV-1 virus Enzyme Oral administration Retroviridae Enzyme inhibitor Inhibitor enzyme complex Organic carbamate Modeling Virus Peptidases Molecular model Force field method Bicyclic compound Hydrolases Lentivirinae Antiviral Aromatic compound Human immunodeficiency virus Chemical synthesis
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Summary:	We have described several potent inhibitors of the HIV-1 protease, based on the novel 3,5-linked bispyrrolinone scaffold which we developed to mimic the peptidal beta -strand/ beta -sheet structural motif. Our most active bispyrrolinone (IC sub(50) 1.3 nM, CIC sub(95) 800 nM) was not orally bioavailable in dogs, reflecting either nonabsorption from the gastrointestinal tract, first-pass metabolism in the liver, or excretion into the bile. The relatively high molecular weight of 735 may account for the poor oral bioavailability. We therefore sought to design and synthesize monopyrrolinone inhibitors of HIV-1 protease with molecular weights <600.
Bibliography:	istex:0FB48AE4290A93545C8FAF9D155F6C78C50E097A ark:/67375/TPS-03FMF3QF-C ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm970195u