Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties

We have developed efficient syntheses of the HIV-1 protease inhibitor 4 and its analogues, which incorporate the pyrrolidone scaffold 2 as P1-P2 moiety. Evaluation of these analogues in the HIV-1 protease enzyme assay resulted in discovery of potent and more water soluble meta-amino- and meta-hydrox...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-11, Vol.14 (22), p.5689-5692
Main Authors: KAZMIERSKI, Wieslaw M, ANDREWS, Webb, FURFINE, Eric, SPALTENSTEIN, Andrew, WRIGHT, Lois
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Drug Design
HIV Protease - drug effects
HIV Protease Inhibitors - chemical synthesis
HIV Protease Inhibitors - chemistry
HIV Protease Inhibitors - pharmacology
Medical sciences
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Pyrrolidinones - chemistry
Structure-Activity Relationship
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Summary:We have developed efficient syntheses of the HIV-1 protease inhibitor 4 and its analogues, which incorporate the pyrrolidone scaffold 2 as P1-P2 moiety. Evaluation of these analogues in the HIV-1 protease enzyme assay resulted in discovery of potent and more water soluble meta-amino- and meta-hydroxy inhibitors 17b and 19b. The SAR observed in this class of PIs could be rationalized with aid of the X-ray structure of inhibitor 28 co-crystallized with the HIV-1 protease, which suggested that the polar meta- (but not para-) benzyl substituents in P2 could side-step the hydrophobic S2 enzyme active pocket by rotating the P2 moiety around its Cbeta-Cgamma bond. Such reorientation allows to engage the unsubstituted, hydrophobic edge of benzyl moiety in P2 in the requisite P2/S2 hydrophobic interaction, and projects polar meta-substituent into the bound water. It appears that the meta-position can be chemically derivatized without potency loss of thus resulting inhibitors, as evidenced by potent 22-26. We thus identified pyrrolidone 2-based inhibitors exemplified by 17b and 19b, which uniquely accommodate both high enzyme potency and which provide a platform for fine-tuning of drug-like properties in this class of PIs by additional chemical manipulations on the meta-position.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.08.039