title: Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N-Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914).
abstract: A novel class of bacterial type-II topoisomerase inhibitor displaying a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold shows potent activity against Gram-positive and fastidious Gram-negative bacteria. Here, we describe a series of N-linked oxazolidinone substituents on the benzisoxazole that improve upon the antibacterial activity of initially described compounds of the class, show favorable PK properties, and demonstrate efficacy in an in vivo Staphylococcus aureus infection model. Inhibition of the topoisomerases DNA gyrase and topoisomerase IV from both Gram-positive and a Gram-negative organisms was demonstrated. Compounds showed a clean in vitro toxicity profile, including no genotoxicity and no bone marrow toxicity at the highest evaluated concentrations or other issues that have been problematic for some fluoroquinolones. Compound 1u was identified for advancement into human clinical trials for treatment of uncomplicated gonorrhea based on a variety of beneficial attributes including the potent activity and the favorable safety profile.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Basarab
authors.forename: Peter
authors.initials: P
authors.lastname: Doig
authors.forename: Vincent
authors.initials: V
authors.lastname: Galullo
authors.forename: Gunther
authors.initials: G
authors.lastname: Kern
authors.forename: Amy
authors.initials: A
authors.lastname: Kimzey
authors.forename: Amy
authors.initials: A
authors.lastname: Kutschke
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Newman
authors.forename: Marshall
authors.initials: M
authors.lastname: Morningstar
authors.forename: John
authors.initials: J
authors.lastname: Mueller
authors.forename: Linda
authors.initials: L
authors.lastname: Otterson
authors.forename: Karthick
authors.initials: K
authors.lastname: Vishwanathan
authors.forename: Fei
authors.initials: F
authors.lastname: Zhou
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Gowravaram
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D008297:Male; D023303:Oxazolidinones / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D007555:Isoxazoles; D023303:Oxazolidinones; D011743:Pyrimidines; D059005:Topoisomerase II Inhibitors