title: Discovery of bacterial NAD⁺-dependent DNA ligase inhibitors: improvements in clearance of adenosine series.
abstract: Optimization of clearance of adenosine inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. To reduce Cytochrome P-450-mediated metabolic clearance, many strategies were explored; however, most modifications resulted in compounds with reduced antibacterial activity and/or unchanged total clearance. The alkyl side chains of the 2-cycloalkoxyadenosines were fluorinated, and compounds with moderate antibacterial activity and favorable pharmacokinetic properties in rat and dog were identified.
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. suzanne.stokes@astrazeneca.com
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Stokes
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Gowravaram
authors.forename: Hoan
authors.initials: H
authors.lastname: Huynh
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: George B
authors.initials: GB
authors.lastname: Mullen
authors.forename: Brendan
authors.initials: B
authors.lastname: Chen
authors.forename: Robert
authors.initials: R
authors.lastname: Albert
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: O'Shea
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rooney
authors.forename: Haiqing
authors.initials: H
authors.lastname: Hu
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Newman
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mills
mesh_terms: D000225:Adenine / Q000737:chemistry; D000241:Adenosine / Q000737:chemistry*; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001682:Biological Availability; D002853:Chromatography, Liquid / Q000379:methods; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005461:Fluorine / Q000737:chemistry; D020128:Inhibitory Concentration 50; D013058:Mass Spectrometry / Q000379:methods; D008956:Models, Chemical; D009243:NAD / Q000737:chemistry*; D051381:Rats
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009243:NAD; D005461:Fluorine; D011088:DNA Ligases; D000225:Adenine; D000241:Adenosine