Discovery of LFF571: AnInvestigational Agent for Clostridium difficileInfection.

Clostridium difficile(C. difficile) is a Gram positive, anaerobic bacterium that infects the lumenof the large intestine and produces toxins. This results in a rangeof syndromes from mild diarrhea to severe toxic megacolon and death.Alarmingly, the prevalence and severity of C. difficileinfection are increasing; thus, associated morbidity and mortalityrates are rising. 4-Aminothiazolyl analogues of the antibiotic naturalproduct GE2270 A (1) were designed, synthesized, andoptimized for the treatment of C. difficileinfection.The medicinal chemistry effort focused on enhancing aqueous solubilityrelative to that of the natural product and previous development candidates(2, 3) and improving antibacterial activity.Structure–activity relationships, cocrystallographic interactions,pharmacokinetics, and efficacy in animal models of infection werecharacterized. These studies identified a series of dicarboxylic acidderivatives, which enhanced solubility/efficacy profile by severalorders of magnitude compared to previously studied compounds and ledto the selection of LFF571 (4) as an investigationalnew drug for treating C. difficileinfection. [ABSTRACT FROM AUTHOR]