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).

@article{Watterson2007AcridonebasedIO,
  title={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).},
  author={Scott H Watterson and Ping Chen and Yufen Zhao and Henry H. Gu and T. G. Murali Dhar and Zili Xiao and Shelley K. Ballentine and Zhongqi Shen and Catherine A. Fleener and Katherine Rouleau and Mary T. Obermeier and Zheng Yang and Kim W McIntyre and David J. Shuster and M. R. Witmer and Donna M. Dambach and Sam T. Chao and Arvind Mathur and Bang-Chi Chen and Joel C. Barrish and Jeffrey A. Robl and Robert M Townsend and Edwin Jan Iwanowicz},
  journal={Journal of medicinal chemistry},
  year={2007},
  volume={50 15},
  pages={
          3730-42
        }
}
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… Expand
Inosine-5’-monophosphate dehydrogenase (IMPDH) inhibitors: a patent and scientific literature review (2002-2016)
TLDR
Progress has been made in the development of IMPDH inhibitors, particularly compounds that are structurally distinct from mycophenolic acid and nucleoside-based inhibitors, however, clinical progression has been hampered primarily by a limited understanding of the enzyme’s role in disease pathophysiology. Expand
10-(4-Phenylpiperazine-1-carbonyl)acridin-9(10H)-ones and Related Compounds: Synthesis, Antiproliferative Activity and Inhibition of Tubulin Polymerization.
TLDR
This work proves the excellent suitability of the acridone scaffold for the design of potent tubulin polymerization inhibitors but also enables synthetic access to further potentially interesting N-acylated acridones. Expand
Myricetin is a novel inhibitor of human inosine 5'-monophosphate dehydrogenase with anti-leukemia activity.
TLDR
Results indicate that natural product myricetin exhibits potent anti-leukemia activity by interfering with purine nucleotides biosynthetic pathway through the suppression of hIMPDH1/2 catalytic activity. Expand
Effect of the inosine 5'-monophosphate dehydrogenase inhibitor BMS-566419 on rat cardiac allograft rejection.
TLDR
The results suggest that BMS-566419 and other chemically synthesized IMPDH inhibitors have beneficial pharmacological effects similar to those of MMF, and are potential pharmaceutical candidates in transplant indications. Expand
Azaindenoisoquinolines as topoisomerase I inhibitors and potential anticancer agents: a systematic study of structure-activity relationships.
TLDR
The present study shows that 7-azaindenoisoquinolines possess the greatest Top1 inhibitory activity and cytotoxicity, and the introduction of a methoxy group into the D-ring of 7-azerous improved their biological activities, leading to new lead molecules for further development. Expand
Structure-activity relationship studies of acridones as potential antipsoriatic agents. 2. Synthesis and antiproliferative activity of 10-substituted hydroxy-10H-acridin-9-ones against human keratinocyte growth.
TLDR
A series of 10-substituted hydroxy-10H-acridin-9-ones were synthesized and studied as potential antipsoriatic agents and Benzyl substitution at the 10-position yielded keratinocyte growth inhibitory activity in the low micromolar range. Expand
In vitro and in vivo characterization of AS2643361, a novel and highly potent inosine 5'-monophosphate dehydrogenase inhibitor.
TLDR
Results suggest AS2643361 has higher potency and less toxicity than MMF, making it a potential candidate for treatment of acute and chronic rejection in transplant medicine. Expand
Effect of the inosine 5'-monophosphate dehydrogenase inhibitor BMS-566419 on renal fibrosis in unilateral ureteral obstruction in rats.
TLDR
Evaluated the antifibrotic effects of BMS-566419 using an experimental rat model, unilateral ureteral obstruction, and other chemically synthesized IMPDH inhibitors have beneficial pharmacological effects similar to those of MMF, and are potential pharmaceutical candidates in the treatment of fibrotic renal disease, including CAN. Expand
Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors
TLDR
This review describes synthesis and biological activity evaluations of the newly designed IMPDH inhibitors and some of the recently reported analogs exhibited promising results during in vitro and in vivo examinations in comparison to substances applied in clinic. Expand
Novel inhibitors of inosine monophosphate dehydrogenase in patent literature of the last decade.
TLDR
The level of newly published patent applications covering IMPDH inhibitors remains high and a diverse range of scaffolds has been claimed. Expand
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It is demonstrated that VX-148 is a potent and specific IMPDH inhibitor with a favorable pharmacokinetic profile and good pharmacological activity in mice, and thus support development of V X-148 as an immunosuppressive drug. Expand
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It is demonstrated that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation in this model of immune activation. Expand
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This review will highlight recent advances in the IMPDH field, with a focus on the discovery and development of non-nucleoside IM PDH inhibitors. Expand
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Inosine 5 -monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme for the synthesis of GTP and dGTP that plays an important role in the expression of cellular genes, such as p53, c-myc and Ki-ras. Expand
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A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase, based upon a 3-cyanoindole core, were explored, and the synthesis and the structure-activity relationships (SAR) derived from in vitro studies, for this new series of inhibitors are given. Expand
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The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors ofExpand
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A series of novel guanidine-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored, which are a target for anticancer, immunosuppressive and antiviral therapy. Expand
IMP dehydrogenase, an enzyme linked with proliferation and malignancy
TLDR
Investigation on purine metabolism showed that in the hepatomas there was an increased capacity in the de novo pathway of biosynthesis of inosine 5′-monophosphate (IMP), as reflected in the increased activity of glutamine PRPP amidotransferase and a decrease in IMP catabolism. Expand
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Screening of our in-house compound collection led to the discovery of 5-bromo-6-amino-2-isoquinoline 1 as a weak inhibitor of IMPDH. Subsequent optimization of 1 afforded a series of novelExpand
Quinazolinethiones and quinazolinediones, novel inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.
The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values forExpand
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