- Acridone-based inhibitors of inosine 5′-monophosphate dehydrogenase: Discovery and SAR leading to the identification of N-(2-(6-(4-ethylpiperazin-1- yl)pyridin-3-yl)propan-2-yl)-2-fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide (BMS-566419)
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Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5′- monophosphate to xanthosine-5′-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.
- Watterson, Scott H.,Chen, Ping,Zhao, Yufen,Gu, Henry H.,Dhar, T. G. Murali,Xiao, Zili,Ballentine, Shelley K.,Shen, Zhongqi,Fleener, Catherine A.,Rouleau, Katherine A.,Obermeier, Mary,Yang, Zheng,McIntyre, Kim W.,Shuster, David J.,Witmer, Mark,Dambach, Donna,Chao, Sam,Mathur, Arvind,Chen, Bang-Chi,Barrish, Joel C.,Robl, Jeffrey A.,Townsend, Robert,Iwanowicz, Edwin J.
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p. 3730 - 3742
(2008/02/12)
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- Synthesis of substituted 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine as new scaffolds for potential bioactive compounds
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The title compounds having different substituents on the heterocyclic framework were prepared by several methods from 2-acetamido-3-hydroxypyridine. The condensation of 2-protected-amino-3-hydroxypyridine with 2-chloroacrylonitrile or ethyl 2,3-dibromopro
- Henry,Sánchez,Sabatié,Bénéteau,Guillaumet,Pujol
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p. 2405 - 2412
(2007/10/03)
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- The first enantioselective synthesis of 4-acetyl-3(R)- and 3(S)-(hydroxymethyl)-3,4-dihydro-2H-pyrido[3,2-b]oxazine
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A novel short and enantioselective synthetic approach to pyridobenzoxazines is reported in which (R)- and (S)-3-(hydroxymethyl)-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazine were first synthesized from readily available chiral glycidyl derivatives.
- Henry,Guillaumet,Pujol
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p. 1465 - 1468
(2007/10/03)
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- FACILE SYNTHESIS OF SOME OXAZOLOPYRIDINES AND THEIR N-OXIDES VIA INTRAMOLECULAR CYCLIZATION
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A convenient synthesis of 3-methylisoxazolopyridine 2, 2-methyloxazolopyridine 4 and their N-oxides (12, 17 and 18) is reported.The configurations of the oximes used for the synthesis of the compounds described above are discussed through chemical and spectral studies.
- Tagawa, Yoshinobu,Goto, Yoshinobu
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p. 2921 - 2939
(2007/10/02)
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