Can I read Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties on EtoBox?

Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties by Wieslaw M. Kazmierski; Webb Andrews; Eric Furfine; Andrew Spaltenstein; Lois Wright is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties about?

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 Cb-Cc 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 propertie

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

Author

Wieslaw M. Kazmierski; Webb Andrews; Eric Furfine; Andrew Spaltenstein; Lois Wright

Publisher

Elsevier Science; Elsevier ; Elsevier Ltd.; Elsevier BV (ISSN 0960-894X)

Published

2004

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)