33252-59-4Relevant articles and documents
Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6)
Singh, Sheo B.,Kaelin, David E.,Wu, Jin,Miesel, Lynn,Tan, Christopher M.,Meinke, Peter T.,Olsen, David B.,Lagrutta, Armando,Wei, Changqing,Liao, Yonggang,Peng, Xuanjia,Wang, Xiu,Fukuda, Hideyuki,Kishii, Ryuta,Takei, Masaya,Yajima, Masanobu,Shibue, Taku,Shibata, Takeshi,Ohata, Kohei,Nishimura, Akinori,Fukuda, Yasumichi
, p. 3636 - 3643 (2015/08/06)
Abstract Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 μM) profile.
Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines
Burgey, Christopher S.,Robinson, Kyle A.,Lyle, Terry A.,Sanderson, Philip E. J.,Lewis, S. Dale,Lucas, Bobby J.,Krueger, Julie A.,Singh, Rominder,Miller-Stein, Cynthia,White, Rebecca B.,Wong, Bradley,Lyle, Elizabeth A.,Williams, Peter D.,Coburn, Craig A.,Dorsey, Bruce D.,Barrow, James C.,Stranieri, Maria T.,Holahan, Marie A.,Sitko, Gary R.,Cook, Jacquelynn J.,McMasters, Daniel R.,McDonough, Colleen M.,Sanders, William M.,Wallace, Audrey A.,Clayton, Franklin C.,Bohn, Dennis,Leonard, Yvonne M.,Detwiler Jr., Theodore J.,Lynch Jr., Joseph J.,Yan, Youwei,Chen, Zhongguo,Kuo, Lawrence,Gardell, Stephen J.,Shafer, Jules A.,Vacca, Joseph P.
, p. 461 - 473 (2007/10/03)
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phen
