Development potential of rifalazil and other benzoxazinorifamycins

Abstract

Rifalazil and other benzoxazinorifamycins (new chemical entities [NCEs]) are rifamycins that contain a distinct planar benzoxazine ring. Rifalazil has excellent antibacterial activity, high intracellular levels and high tissue penetration, which are attributes that favour its use in treating diseases caused by the obligate intracellular pathogens of the genus Chlamydia. Recent studies have shown that rifalazil has efficacy in the treatment of human sexually transmitted disease caused by Chlamydia trachomatis. The extraordinary potency of rifalazil and other NCEs, such as ABI-0043, extends to the related microorganism, C. pneumoniae, a respiratory pathogen that can disseminate and persist chronically in the vasculature, resulting in increased plaque formation in animal studies. A pivotal clinical trial with rifalazil has been initiated for the treatment of peripheral arterial disease. Other opportunities include gastric ulcer disease caused by Helicobacter pylori and antibiotic-associated colitis caused by infection with Clostridium difficile in the colon. The NCEs could prove to be valuable as follow-on compounds in these indications, as rifampin replacements in antibacterial combination therapy or as stand-alone topical antibacterials (e.g., to treat acne). Neither rifalazil nor NCEs appear to induce the cytochrome P450 3A4, an attribute of rifampin that can result in adverse events due to drug-drug interactions.

Rifalazil and Derivative Compounds Show Potent Efficacy in a Mouse Model of H. pylori Colonization

“…3, it appears that there is a systemic component that contributes to efficacy. It is very possible, therefore, that differences between NCEs result from pharmacokinetic differences among these compounds [14,15]. These results are in agreement with studies which indicate that both topical and a systemic component must be considered in efficacy in eradicating H. pylori [16].…”

Rifamycin antibiotic resistance by ADP-ribosylation: Structure and diversity of Arr

“…Rifaximin, a semisynthetic rifamycin, was approved in 2003 for prophylactic use in the treatment of traveler's diarrhea (34). Rifalazil, an analogue with antichlamy-dial activity (35), is in Phase III trials. This rediscovery of the rifamycin antibiotics continues apace, and new semisynthetic rifamycin derivatives are in various stages of development (e.g., refs.…”

Rifalazil Retains Activity Against Rifampin-resistant Mutants of Chlamydia pneumoniae

“…Potency may be important to overcome Chlamydia, which can enter the persistent state, which may be more refractory to many antibiotics [10,11]. Rifalazil has a long half-life and large volume of distribution, properties that may enhance efficacy against these obligate intracellular pathogens in vivo [3,12,13]. Animal studies support this hypothesis.…”

“…More recently rifalazil has been evaluated for treatment of peripheral arterial disease, based on an association of atherosclerosis and C. pneumoniae infection, supported by animal model studies, and investigations showing the presence of C. pneumoniae in diseased vasculature [13,15].…”

“…The rifalazil MIC for even the highest mutant was 0.125 m g/ml. Considering the high intracellular level of rifalazil in mammalian cells [13], an inhibitory concentration of rifalazil may be achievable during clinical use. Thus the physiological concentrations of rifalazil, but not of rifampin, may be sufficient to reduce the selection of mutants.…”