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)

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 mycophen...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-07, Vol.50 (15), p.3730-3742
Main Authors: 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
Format: Article
Language:English
Subjects:
Acridines - chemical synthesis
Acridines - pharmacology
Acridines - toxicity
Administration, Oral
Animals
Arthritis, Experimental - drug therapy
Arthritis, Rheumatoid - drug therapy
Biological Availability
Cell Line
Cell Proliferation
Gastrointestinal Tract - drug effects
Half-Life
Humans
IMP Dehydrogenase - antagonists & inhibitors
Leukocytes, Mononuclear - drug effects
Macaca fascicularis
Male
Piperazines - chemical synthesis
Piperazines - pharmacology
Piperazines - toxicity
Rats
Rats, Inbred Lew
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070299x