Pharmacology and early ADMET data of corallopyronin A, a natural product with macrofilaricidal anti-wolbachial activity in filarial nematodes

Corallopyronin A (CorA), a natural product antibiotic of Corallococcus coralloides , inhibits the bacterial DNA-dependent RNA polymerase. It is active against essential Wolbachia endobacteria filarial nematodes, preventing development, causing sterility and killing adult worms. CorA being developed to treat neglected tropical diseases onchocerciasis lymphatic filariasis caused by -containing filariae. For this, we have completed standard Absorption, Distribution, Metabolism, Excretion Toxicity (ADMET) studies. In Caco-2 assays, had good adsorption values, predicting transport from intestines, but may be subject efflux. fed-state simulated human intestinal fluid (pH 5.0), half-life was >139 minutes, equivalent stability in buffer 7.4). plasma-stability >240 with plasma protein binding >98% human, mouse, rat, dog, mini-pig monkey plasma. Clearance dog liver microsomes low (35.2 42 µl/min/mg, respectively). mainly metabolized via phase I reactions, i.e., oxidation, minimal extent II reactions. contrast rifampicin, does not induce CYP3A4 resulting lower drug-drug-interaction potential. Apart inhibition CYP2C9, no impact on enzymes CYP450 system detected. Off-target profiling resulted three hits (inhibition/activation) for 3 PPARγ receptors COX1 enzyme; thus, potential drug-drug interactions could occur antidiabetic medications, COX2 inhibitors, angiotensin AT1 receptor antagonists, vitamin K-antagonists, antidepressants. vivo pharmacokinetic studies Mongolian gerbils rats demonstrated excellent intraperitoneal oral bioavailability (100%) fast absorption high distribution No significant hERG detected phototoxicity seen. did gene mutations bacteria (Ames test) nor chromosomal damage lymphocytes (micronucleus test). Thus, possesses an acceptable vitro early ADMET profile; supported previous experiments mice, which all animals tolerated daily administration 7-28 days. The non-GLP package will guide selection planning regulatory-conform GLP models prior first-into-human study.