SQ609

Sequella synthesized over 100,000 small molecules to discover new scaffolds with anti-microbacterial activity and identify new leads with sufficient in vitro and in vivo activity against M. tuberculosis (Mtb) appropriate pharmacological properties, and suitable toxicity profiles to warrant taking one or more potential new antitubercular drugs into human clinical trials. The libraries were screened for anti-mycobacterial activity by both direct determination of MIC against Mtb H37Rv and a high-throughput assay with recombinant Mycobacteria containing luciferase (Luc) fused to a promoter, Rv0341, which controls genes that are strongly induced upon treatment by cell wall inhibitors such as ethambutol, isoniazid, and ethionamide. This screen identified a new series of potent cell-wall inhibiting dipiperidines that are structurally unrelated to any existing antitubercular drugs or new drug candidates. After lead optimization studies and extensive analysis of the dipiperidine pharmacophore for antimicrobial activity and drug properties, the compound SQ609 was selected as the most promising in the class. SUMMARY OF ITS ATTRIBUTES INCLUDE: Potent in vitro activity against laboratory and clinical strains of M.tuberculosis. Inhibition of M. tuberculosis by interfering with cell wall biosynthesis. Moderate in vitro cytotoxicity in cultured mammalian cells. Suitable therapeutic window (in vitro). Active against intracellular Mtb. High specificity for M. tuberculosis. Good aqueous solubility. Orally bioavailable. Active against M.tuberculosis in two different mouse models of TB upon oral administration. Able to prolong therapeutic effect after the withdrawal of drug therapy in mice. Promising activity against M. tuberculosis when administered in combination with INH, RIF, and PZA. Favorable in vitro safety pharmacology and ADME profile.