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Research and Development - Results
The development of novel antibacterial agents derived from inhibition of new targets has been a notoriously difficult challenge for both academic and pharmaceutical industry scientists. MaxThera’s approach, integrating the disciplines of enzymology, medicinal chemistry and microbiology, has afforded consistent forward progress toward the clinic with multiple new target programs.
As with most target screening programs, MaxThera’s initial screening hits and early target lead compounds were exceptionally potent enzyme inhibitors - but the physical chemical properties of these compounds were incompatible with human bioavailability or with bacterial cell penetration.
Subsequent iterations of inhibitor synthesis and design have produced inhibitors with dramatically improved properties that have demonstrated antibacterial activity in the therapeutic range. The ongoing evolution of antibacterial potency for MaxThera’s novel antibacterial target inhibitors is illustrated on Chart 1.
MaxThera scientists continually monitor an array of secondary assays to assess ‘druggability’ of the inhibitor analogs throughout Lead Optimization. Representative cytotoxicity data derive from in vitro cellular experiments with 3T3 and HepG2, including data control drugs, cells are illustrated in Chart 2.
The treatment of infections due to Gram-negative pathogens is becoming increasingly problematic due to rapidly growing resistance coupled with a conspicuous lack of new G- drugs in development. The Gram-negative outer membrane adds a layer of complexity to new drug development that is often manifested in the relative ease with which Gram-positive activity can be achieved. With this in mind, in 2007, MaxThera began to modify inhibitor structures with Gram-negative cell penetration in mind. The progress illustrated to date is illustrated in Chart 3.
Avoiding antibiotic resistance is a critical component of MaxThera’s approach to antibacterial drug discovery. The MT274 Lead Optimization program targets EPT (MurA) - the biochemical target of fosfomycin (Monurol - Forest Pharmaceuticals, Inc.), providing an important opportunity to track progress against a known drug. To date, MaxThera’s EPT inhibitors have demonstrated good potency against both fosfomycin resistant and susceptible strains, with no signs of cross resistance (Chart 4).
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