Design, synthesis and activity of a potent, selective series of N -aryl pyridinone inhibitors of p38 kinase

Selness, Shaun R.; 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; Devraj, Rajesh; Messing, Dean; Schindler, John F.; Hirsch, Jeffrey L.; Saabye, Matthew J; Bonar, Sheri L.; Webb, Elizabeth; Anderson, Gary D.; Monahan, Joseph B.

doi:10.1016/j.bmcl.2011.04.120

Cited by 15 publications

(4 citation statements)

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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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“…To understand the mechanistic hypothesis, a preformed 6-methyl-1-phenylpyridine-2,4(1 H ,3 H )-dione 8 , 18 derived from 4-hydroxy-6-methyl-2 H -pyran-2-one and aniline, was reacted with 1c and 2a under the standard conditions. The corresponding tricyclic product 5f was obtained in 75% yield (Scheme 5, eq 1).…”

Section: Resultsmentioning

confidence: 99%

Four-Component Bicyclization Approaches to Skeletally Diverse Pyrazolo[3,4-b]pyridine Derivatives

Hao

et al. 2014

J. Org. Chem.

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A novel four-component bicyclization strategy has been established, allowing a flexible and practical approach to 37 examples of multicyclic pyrazolo[3,4-b]pyridines from low-cost and readily accessible arylglyoxals, pyrazol-5-amines, aromatic amines, 4-hydroxy-6-methyl-2H-pyran-2-one, and cyclohexane-1,3-diones. The polysubstituted cyclopenta[d]pyrazolo[3,4-b]pyridines were stereoselectively synthesized through a microwave-assisted special [3+2+1]/[3+2] bicyclization with good control of the spatial configuration of exocyclic double bonds. The novel [3+2+1]/[2+2+1] bicyclization resulted in 17 examples of unreported pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones. Reasonable mechanisms for forming two new types of multicyclic pyrazolo[3,4-b]pyridines are also proposed.

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“…To tackle this issue, the N-benzyl group was modified, converting it into a monosubstituted N-aryl group, which resulted in the development of a metabolically stable inhibitor 65. 64 Subsequently, Selness hypothesized the existence of an orthogonal relationship between the pyridinone and N-aryl rings. Therefore, in 2011, the research team described their work on designing and synthesizing a novel conformationally restricted p38 inhibitor (-)-66.…”

Section: C-n Bonded Axial Chirality Bioactive Compoundsmentioning

confidence: 99%

Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery

Liu,

Zhao,

Liu

et al. 2024

Medicinal Research Reviews

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Atropisomerism, an expression of axial chirality caused by limited bond rotation, is a prominent aspect within the field of medicinal chemistry. It has been shown that atropisomers of a wide range of compounds, including established FDA‐approved drugs and experimental molecules, display markedly different biological activities. The time‐dependent reversal of chirality in atropisomers poses complexity and obstacles in the process of drug discovery and development. Nonetheless, recent progress in understanding atropisomerism and enhanced characterization methods have greatly assisted medicinal chemists in the effective development of atropisomeric drug molecules. This article provides a comprehensive review of their special design thoughts, synthetic routes, and biological activities, serving as a reference for the synthesis and biological evaluation of bioactive atropisomers in the future.

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Design, synthesis and activity of a potent, selective series of N -aryl pyridinone inhibitors of p38 kinase

Cited by 15 publications

References 8 publications

Clinical candidates of small molecule p38 MAPK inhibitors for inflammatory diseases

Clinical candidates of small molecule p38 MAPK inhibitors for inflammatory diseases

Four-Component Bicyclization Approaches to Skeletally Diverse Pyrazolo[3,4-b]pyridine Derivatives

Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery

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