Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase

Selness, Shaun R.; Devraj, Rajesh; Monahan, Joseph B.; Boehm, Terri L.; Walker, John K.; Devadas, Balekudru; Durley, Richard C.; Kurumbail, Ravi G.; Shieh, Huey‐Sheng; Li, Xing; Hepperle, Michael; Rucker, Paul V.; Jerome, Kevin D.; Benson, Alan G.; Marrufo, Laura D.; Madsen, Heather M.; Hitchcock, Jeff; Owen, Tom J.; Christie, Lance C.; Promo, Michele A.; Hickory, Brian S.; Alvira, Edgardo; Naing, Win; Blevis-Bal, Radhika

doi:10.1016/j.bmcl.2009.08.082

Cited by 27 publications

(10 citation statements)

References 12 publications

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“…Follow-on to SD-0006 the lead generation and optimization efforts led to the identification of a novel pharmacophore PH-797804 as a clinical candidate for RA and COPD. [63][64][65][66] First identified by molecular modeling and subsequently confirmed by chiral chromatography, PH-797804 is the more potent atropisomer (aS) of a racemic pair. 63 In biochemical assays and as well as assays PH-797804 demonstrated high potency cellular (Ki=5.8 nM) and superior selectivity across broad human kinase genome.…”

Section: Reviewmentioning

confidence: 99%

Clinical candidates of small molecule p38 MAPK inhibitors for inflammatory diseases

2016

MAP Kinase

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The trigger and etiology of chronic inflammatory diseases are not well understood, hindering the development of efficient therapeutic approaches. The observation that abnormal activity of the p38 MAPK is common to all inflammatory diseases raised the expectation that p38 inhibitors would serve as general anti-inflammatory therapeutics. A large number of inhibitors were consequently discovered. Several compounds of different scaffolds, blocking the p38 MAPK signaling pathway, have entered phase II clinical trials for rheumatoid arthritis, chronic obstructive pulmonary disease, pain, cardiovascular diseases, and cancer. As I review here, in almost all cases the clinical trials have failed, leading to re-design of compounds and re-evaluation of p38 as a suitable target. I describe how structural features, unique to p38<span>α</span>, have been employed in the inhibitor design and achieved high degree of kinome selectivity. I then focus on some of the drugs that reached human trials and summarize their <em>in vitro/in vivo</em> pharmacological profiles and the related outcomes from clinical investigations. These compounds include VX-745, VX-702, RO-4402257, SCIO- 469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323 and GW-856553. Finally, I discuss novel suggested approaches for the use of p38 inhibitors such as combining p38 inhibition with inhibiting other targets that function in parallel inflammatory pathways for achieving efficacy in treating inflammatory diseases.

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Section: Reviewmentioning

confidence: 99%

Clinical candidates of small molecule p38 MAPK inhibitors for inflammatory diseases

2016

MAP Kinase

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“…On this basis, the ability of the ligand to induce the Gly flip at the hinge region has been reported as one of the determinant factors for the high degree of p38α selectivity achieved by some of the analyzed TI‐Is (i.e., 6 , 21 , 22 , 24 , 35 , 36 , 44 , 46 , 48 , 51 , 52 , 61 , 64 , 65 , 67 , and 73 ) 7. 10, 15a, 16d, f, h, 17d–f, 18a, 19, 21a, 43 In contrast with this hypothesis, recent findings by Watterson et al. have indicated that a ligand′s ability to induce the Gly flip conformational change is not a key factor in generating selectivity, as demonstrated for compounds 10 and 11 15b…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Structural Overview of p38α MAPK in Complex with Type I Inhibitors

et al. 2015

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p38α mitogen-activated protein kinase (MAPK) is a well-recognized therapeutic target for the treatment of autoimmune and inflammatory diseases. Over the past two decades, tremendous efforts have been focused on the discovery and development of small-molecule p38α MAPK inhibitors, although currently no drugs targeting this protein are clinically available. Therefore, the identification of novel chemotypes that are able to inhibit p38α MAPK function is still of great therapeutic significance. With the objective to support drug discovery programs aimed at identifying new immunomodulators acting on p38α MAPK, herein we present a complete overview of the available crystal structures of this protein in complex with ATP-site type I inhibitors. The 85 available complexes are classified by chemotype and experimental binding mode, and the ligand-protein interactions are discussed using the most representative inhibitors. The type and frequency of key inhibitor features are analyzed to give a final summary of the chemical requirements of promising p38α MAPK inhibitors. The proposed pharmacophore can be exploited to enhance the opportunities to identify novel type I inhibitors of p38α MAPK.

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“…The combined organic layers were dried over Na 2 SO 4 . The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash chromatography over silica gel with CH 2 Cl 2 −acetone (3:1) to give 17 as white solid (26.9 mg, 88% yield) Recrystallization from CH 2 Cl 2 −hexane gave pure 17 as colorless crystals: 1 (18). To a stirred solution of 16 (103 mg, 0.178 mmol) and imidazole (54.4 mg, 0.799 mmol) in DMF (0.59 mL) was added chlorotriethylsilane (0.0890 mL, 0.533 mmol) at 0 °C.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…2-Pyridinone derivative 10 was easily accessible from commercially available 4-chloropyridine Noxide 9. 17,18 The selective stepwise bromination and iodination gave the desired coupling precursor 11 in high yield. 19 With the requisite coupling precursors in hand, we went on to investigate the palladium catalyzed coupling reaction between the cyclopentenone derivative and the hydroxy-2pyridinone core.…”

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Synthetic Studies on FNC-RED and Its Analogues Containing an All syn-Cyclopentanetetrol Moiety

et al. 2019

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Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase

Cited by 27 publications

References 12 publications

Clinical candidates of small molecule p38 MAPK inhibitors for inflammatory diseases

Clinical candidates of small molecule p38 MAPK inhibitors for inflammatory diseases

A Comprehensive Structural Overview of p38α MAPK in Complex with Type I Inhibitors

Synthetic Studies on FNC-RED and Its Analogues Containing an All syn-Cyclopentanetetrol Moiety

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