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Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization.

Deng JZ, McMasters DR, Rabbat PM, Williams PD, Coburn CA, Yan Y, Kuo LC, Lewis SD, Lucas BJ, Krueger JA, Strulovici B, Vacca JP, Lyle TA, Burgey CS
Bioorg Med Chem Lett 15 4411-6 (2005)
Cited: 13 times
EuropePMC logo PMID: 16137886

Abstract

Thrombin-inhibitor X-ray crystal structures, in combination with the installation of binding elements optimized within the pyrazinone series of thrombin inhibitors, were utilized to transform a weak triazolopyrimidine lead into a series of potent oxazolopyridines. A modification intended to attenuate plasma protein binding (i.e., conversion of the P3 pyridine to a piperidine) conferred significant factor Xa activity to this series. Ultimately, these dual thrombin/factor Xa inhibitors demonstrated excellent in vitro and in vivo anticoagulant efficacy.

Articles - 1zgv mentioned but not cited (1)

  1. Knowledge-guided docking: accurate prospective prediction of bound configurations of novel ligands using Surflex-Dock. Cleves AE, Jain AN. J. Comput. Aided Mol. Des. 29 485-509 (2015)


Reviews citing this publication (3)

  1. Oral, direct thrombin and factor Xa inhibitors: the replacement for warfarin, leeches, and pig intestines? Straub A, Roehrig S, Hillisch A. Angew. Chem. Int. Ed. Engl. 50 4574-4590 (2011)
  2. Structure-activity relationship studies for multitarget antithrombotic drugs. Neves AR, Correia-da-Silva M, Sousa E, Pinto M. Future Med Chem 8 2305-2355 (2016)
  3. Antithrombotics from the Sea: Polysaccharides and Beyond. Carvalhal F, Cristelo RR, Resende DISP, Pinto MMM, Sousa E, Correia-da-Silva M. Mar Drugs 17 (2019)

Articles citing this publication (9)

  1. Selective and dual action orally active inhibitors of thrombin and factor Xa. Young RJ, Brown D, Burns-Kurtis CL, Chan C, Convery MA, Hubbard JA, Kelly HA, Pateman AJ, Patikis A, Senger S, Shah GP, Toomey JR, Watson NS, Zhou P. Bioorg. Med. Chem. Lett. 17 2927-2930 (2007)
  2. From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3. Dönnecke D, Schweinitz A, Stürzebecher A, Steinmetzer P, Schuster M, Stürzebecher U, Nicklisch S, Stürzebecher J, Steinmetzer T. Bioorg. Med. Chem. Lett. 17 3322-3329 (2007)
  3. Highly potent and selective substrate analogue factor Xa inhibitors containing D-homophenylalanine analogues as P3 residue: part 2. Stürzebecher A, Dönnecke D, Schweinitz A, Schuster O, Steinmetzer P, Stürzebecher U, Kotthaus J, Clement B, Stürzebecher J, Steinmetzer T. ChemMedChem 2 1043-1053 (2007)
  4. Comparative biotransformation of pyrazinone-containing corticotropin-releasing factor receptor-1 antagonists: minimizing the reactive metabolite formation. Zhuo X, Hartz RA, Bronson JJ, Wong H, Ahuja VT, Vrudhula VM, Leet JE, Huang S, Macor JE, Shu YZ. Drug Metab Dispos 38 5-15 (2010)
  5. Strong nonadditivity as a key structure-activity relationship feature: distinguishing structural changes from assay artifacts. Kramer C, Fuchs JE, Liedl KR. J Chem Inf Model 55 483-494 (2015)
  6. New therapeutic option for thromboembolism--dabigatran etexilate. Nishio H, Ieko M, Nakabayashi T. Expert Opin Pharmacother 9 2509-2517 (2008)
  7. Synthesis and fungicidal activities of new 1,2,4-triazolo[1,5-a]pyrimidines. Chen Q, Liu ZM, Chen CN, Jiang LL, Yang GF. Chem. Biodivers. 6 1254-1265 (2009)
  8. Efficient regioselective five-component synthesis of novel thiazolo[3,2-a]pyridine carbohydrazides and oxazolo[3,2-a]pyridine carbohydrazides. Rouzban H, Bayat M, Hosseini H. Mol Divers 27 667-678 (2023)
  9. Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-Amidino and Amidino N²-Thiophenecarbonyl- and N²-Tosylanthranilamides. Lee SH, Lee W, Nguyen T, Um IS, Bae JS, Ma E. Int J Mol Sci 18 (2017)


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