1. Development of (6R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis
- Author
-
Thompson, Andrew M, O'Connor, Patrick D, Marshall, Andrew J, Blaser, Adrian, Yardley, Vanessa, Maes, Louis, Gupta, Suman, Launay, Delphine, Braillard, Stephanie, Chatelain, Eric, Wan, Baojie, Franzblau, Scott G, Ma, Zhenkun, Cooper, Christopher B, and Denny, William A
- Subjects
ERG1 Potassium Channel ,Mice, Inbred BALB C ,Cell Membrane Permeability ,Antiparasitic Agents ,Dose-Response Relationship, Drug ,Mesocricetus ,Drug Evaluation, Preclinical ,Microbial Sensitivity Tests ,Mycobacterium tuberculosis ,Article ,Rats ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Cricetinae ,Oxazines ,Animals ,Cytochrome P-450 CYP3A ,Cytochrome P-450 CYP3A Inhibitors ,Leishmaniasis, Visceral ,Chagas Disease ,Leishmania infantum ,Leishmania donovani - Abstract
Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
- Published
- 2018