Discovery of a potent and selective series of pyrazole bacterial methionyl-tRNA synthetase inhibitors.
Starting with a micromolar lead identified from high-throughput screening, a series of pyrazoles were discovered with significantly improved potency on bacterial methionyl-tRNA synthetase and selectivity over human methionyl-tRNA synthetase.
Finn
John
J
Cubist Pharmaceutical Inc., 65 Hayden Ave., 02421, Lexington, MA, USA. john.finn@cubist.com
Mattia
Karen
K
Morytko
Mike
M
Ram
Siya
S
Yang
Yingfei
Y
Wu
Ximao
X
Mak
Elsa
E
Gallant
Paul
P
Keith
Dennis
D
D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011720:Pyrazoles; D008718:Methionine-tRNA Ligase