opc-67683 and Chronic-Disease

Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.

Topics: Administration, Oral; Animals; Antitubercular Agents; Biological Availability; Chemistry Techniques, Synthetic; Chronic Disease; Disease Models, Animal; Humans; Male; Mice, Inbred BALB C; Mice, Inbred Strains; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Rats, Sprague-Dawley; Structure-Activity Relationship; Tuberculosis

Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH(2) linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (∼2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.

Topics: Acute Disease; Amides; Animals; Antitubercular Agents; Biological Availability; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carbamates; Chronic Disease; Dogs; Humans; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Models, Molecular; Mycobacterium tuberculosis; Nitroimidazoles; Piperazines; Rats; Solubility; Stereoisomerism; Structure-Activity Relationship; Tuberculosis, Pulmonary; Urea