title: 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.
authors.affiliation: ActivBiotics, Inc., 110 Hartwell Avenue, Lexington, MA 02421, USA. drothstein@activbiotics.com
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
authors.forename: Christo
authors.initials: C
authors.lastname: Shalish
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Murphy
authors.forename: Andrew
authors.initials: A
authors.lastname: Sternlicht
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Campbell
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000382:microbiology; D002690:Chlamydia Infections / Q000188:drug therapy* / Q000382:microbiology; D002692:Chlamydia trachomatis / Q000187:drug effects / Q000302:isolation & purification; D016993:Chlamydophila pneumoniae / Q000187:drug effects / Q000302:isolation & purification; D002691:Chlamydophila psittaci / Q000187:drug effects / Q000302:isolation & purification; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000382:microbiology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D016032:Randomized Controlled Trials as Topic; D012294:Rifamycins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D012294:Rifamycins; C068980:KRM 1648