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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)

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)

Scott H Watterson, Ping Chen, Yufen Zhao, Henry H Gu, T G Murali Dhar, Zili Xiao, Shelley K Ballentine, Zhongqi Shen, Catherine A Fleener, Katherine A Rouleau, Mary Obermeier, Zheng Yang, Kim W McIntyre, etc.

J Med Chem. 2007 Jul 26;50(15):3730-42.

PMID: 17585753

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
CS31042414	Mycophenolate Mofetil Related Compound A			Price

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