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-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.
GlaxoSmithKline Research, 5 Moore Drive, Research Triangle Park, NC 27709, USA. wieslaw.m.kazmierski@gsk.com
Wieslaw M
WM
Kazmierski
Webb
W
Andrews
Eric
E
Furfine
Andrew
A
Spaltenstein
Lois
L
Wright
D015195:Drug Design; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D011760:Pyrrolidinones / Q000737:chemistry*; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D011760:Pyrrolidinones; D016333:HIV Protease