Semisynthetic derivatives of minocycline with improved activity against tetracycline-resistant bacteria include tigecycline, a 9-substituted glycylcycline,  and omadacycline, an aminomethylcycline. We have made multiple novel classes (e.g., 8-azatetracyclines; 8,9-pentacyclines; 7-fluorosancycline compounds with unique 9-substitutions) by extending the total synthetic methodology developed by Myers, et al..  A tandem Michael-Dieckmann condensation between a D-ring precursor and an enone forming the AB rings of the tetracyclic nucleus affords the 7-fluorocyclines in sufficient quantities with appropriate chemical protection to allow for efficient analoging.  TP-434, our most advanced candidate, arose from these efforts.  It has a broad antimicrobial spectrum in vitro including all multidrug-resistant gram-negative and gram-positive aerobic and anaerobic bacteria except Pseudomonas aeruginosa.  TP-434 protects in key murine infection models and is orally bioavailable in humans with a long half-life consistent with once-daily dosing. The intravenous formulation of TP-434 is currently in phase 2 clinical trials for treatment of complicated intra-abdominal infections.

TP-434 is a fully synthetic tetracycline designed for troublesome hospital pathogens

244th National Meeting (2012)

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