title: Pharmaceutical salt of BM635 with improved bioavailability.
abstract: BM635 is a small molecule endowed with outstanding anti-mycobacterial activity (minimum inhibitory concentration of 0.12μM against M. tuberculosis H37Rv) identified during a hit-to-lead campaign. Its poor aqueous solubility together with its high lipophilicity led to low exposure in vivo. Indeed, the half-life in vivo of BM635 was 1h, allowing a reasonable maximum concentration (Cmax=1.62μM) and a moderate bioavailability (46%). The present study aimed to develop salt forms of BM635 with pharmaceutically accepted hydrochloric, methanesulphonic, phosphoric, tartaric, and citric acids to overcome these drawbacks. BM635 salts (BM635-HCl, BM635-Mes, BM635-PA, BM635-TA and BM635-CA) were evaluated for physicochemical as well as biopharmaceutical attributes.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, Rome, Italy. Electronic address: giovanna.poce@uniroma1.it.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Poce
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Consalvi
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, Rome, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Cocozza
authors.affiliation: Diseases of the Developing World, Tres Cantos Medicines Development Campus, GSK, Tres Cantos, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Fernandez-Menendez
authors.affiliation: Diseases of the Developing World, Tres Cantos Medicines Development Campus, GSK, Tres Cantos, Madrid, Spain.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bates
authors.affiliation: Diseases of the Developing World, Tres Cantos Medicines Development Campus, GSK, Tres Cantos, Madrid, Spain.
authors.forename: Fátima
authors.initials: F
authors.lastname: Ortega Muro
authors.affiliation: Diseases of the Developing World, Tres Cantos Medicines Development Campus, GSK, Tres Cantos, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Barros Aguirre
authors.affiliation: Diseases of the Developing World, Tres Cantos Medicines Development Campus, GSK, Tres Cantos, Madrid, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Ballell
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, Rome, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001682:Biological Availability; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012492:Salts / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D012492:Salts; D014867:Water
keywords: BM635; Drug development; MmpL3; Pharmaceutical salts; Tuberculosis