Design and synthesis of 2′-anilino-4,4′-bipyridines as selective inhibitors of c-Jun N-terminal kinase-3

Swahn, Britt‐Marie; Xue, Yafeng; Arzel, Erwan; Kallin, Elisabet; Magnus, Angelika S.; Plobeck, Niklas; Viklund, Jenny

doi:10.1016/j.bmcl.2005.11.039

Cited by 51 publications

(43 citation statements)

References 26 publications

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“…Due to the nature of the compound wrapping itself around the hinge region, the limited contacts allowed the P-loop to be flexible in the crystal to the point that residues 71-75 in beta strand 1 were untraceable at 1 sigma electron density contour level. This flexibility and break in the chain have been seen in previous JNK3 structures (15,22,25,32,34,46). SR-3737 and SR-3451 bound in the ATP pocket of JNK3 in a very similar and well defined fashion.…”

Section: Jnk3/p38 Sar For Indazole-based Inhibitors-supplementalmentioning

confidence: 54%

“…In contrast to p38, there have been fewer reports for selective JNK inhibitors, and the clinical development of JNK inhibitors also lags that of p38. Despite the paucity of highly selective JNK inhibitors that have advanced to clinical development, numerous recent reports have begun to emerge that show compounds from various structural classes (benzothiazole pyrimidines, aminopyridines, benzothien-2-yl amides, aminopyrimidines, and quinolines) having selectivity for JNK over p38 (5,15,17,(22)(23)(24). The well described toxicity of p38 inhibition (7) necessitates this desired selectivity in any JNK inhibitor program.…”

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confidence: 99%

“…p38 especially has garnered considerable interest, particularly for the treatment of rheumatoid arthritis and Crohn disease, and numerous compounds have entered clinical trials for these indications (7)(8)(9)(10)(11). Because most of the p38 inhibitors are competitive versus ATP (12)(13)(14)(15)(16)(17), and there are 518 kinases in the genome, it was crucial to develop compounds that are selective against a broad panel of kinases so that compounds could be advanced to clinical development. The molecular basis that gives rise to selective p38 inhibitors from numerous structural classes has been reported (18 -20) and is centered on amino acid differences at the so-called "gatekeeper" Thr-106 residue in p38 (Met in all of the JNK isoforms and Gln in extracellular regulated kinase, the other mitogenactivated protein kinase family member).…”

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confidence: 99%

“…Given the compelling validation data for JNK as a drug target and the emergence of a few structural classes of JNK selective compounds that have been reported (15,17,(22)(23)(24), we set out to investigate whether JNK inhibitor selectivity over p38 could be established. We started our efforts with an indazole class of compounds and were not able to establish significant selectivity for JNK3 over p38.…”

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confidence: 99%

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Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Kamenecka

Habel

Duckett

et al. 2009

Journal of Biological Chemistry

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c-Jun N-terminal kinase 3␣1 (JNK3␣1) is a mitogen-activated protein kinase family member expressed primarily in the brain that phosphorylates protein transcription factors, including c-Jun and activating transcription factor-2 (ATF-2) upon activation by a variety of stress-based stimuli. In this study, we set out to design JNK3-selective inhibitors that had >1000-fold selectivity over p38, another closely related mitogen-activated protein kinase family member. To do this we employed traditional medicinal chemistry principles coupled with structurebased drug design. Inhibitors from the aminopyrazole class, such as SR-3576, were found to be very potent JNK3 inhibitors (IC 50 ‫؍‬ 7 nM) with >2800-fold selectivity over p38 (p38 IC 50 > 20 M) and had cell-based potency of ϳ1 M. In contrast, indazole-based inhibitors exemplified by SR-3737 were potent inhibitors of both JNK3 (IC 50 ‫؍‬ 12 nM) and p38 (IC 50 ‫؍‬ 3 nM). These selectivity differences between the indazole class and the aminopyrazole class came despite nearly identical binding (root mean square deviation ‫؍‬ 0.33 Å ) of these two compound classes to JNK3. The structural features within the compounds giving rise to the selectivity in the aminopyrazole class include the highly planar nature of the pyrazole, N-linked phenyl structures, which better occupied the smaller active site of JNK3 compared with the larger active site of p38.Because the initial reports on the discovery of p38 (1) and c-Jun N-terminal kinase (JNK) 2 (2-6) these mitogen-activated protein kinase family members have generated great interest as drug targets. p38 especially has garnered considerable interest, particularly for the treatment of rheumatoid arthritis and Crohn disease, and numerous compounds have entered clinical trials for these indications (7-11). Because most of the p38 inhibitors are competitive versus ATP (12-17), and there are 518 kinases in the genome, it was crucial to develop compounds that are selective against a broad panel of kinases so that compounds could be advanced to clinical development. The molecular basis that gives rise to selective p38 inhibitors from numerous structural classes has been reported (18 -20) and is centered on amino acid differences at the so-called "gatekeeper" Thr-106 residue in p38 (Met in all of the JNK isoforms and Gln in extracellular regulated kinase, the other mitogenactivated protein kinase family member). Many compounds have been synthesized that take advantage of this deeper hydrophobic pocket in p38, compared with JNK3, and the structures of the compounds have included trifluoromethyl and other large moieties, which all contribute to p38 selectivity (21). In contrast to p38, there have been fewer reports for selective JNK inhibitors, and the clinical development of JNK inhibitors also lags that of p38. Despite the paucity of highly selective JNK inhibitors that have advanced to clinical development, numerous recent reports have begun to emerge that show compounds from various structural classes (benzothiazole pyrimidines, aminopyr...

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Section: Jnk3/p38 Sar For Indazole-based Inhibitors-supplementalmentioning

confidence: 54%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Kamenecka

Habel

Duckett

et al. 2009

Journal of Biological Chemistry

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“…Compound classes that have shown nice JNK selectivity include: aminopyrazoles13, aminopyridines14, 15, pyridine carboxamides15, 16, benzothien-2-yl-amides and benzothiazol-2-yl acetonitriles 17, 18, quinoline derivatives19, and aminopyrimidines 20–22. For a recent review of all these classes see LoGrasso and Kamenecka 23.…”

mentioning

confidence: 99%

Synthesis and SAR of novel quinazolines as potent and brain-penetrant c-jun N-terminal kinase (JNK) Inhibitors

Kamenecka

Shin

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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Quinazoline 3 was discovered as a novel c-jun N-terminal kinase (JNK) inhibitor with good brain penetration and pharmacokinetic (PK) properties. A number of analogs which were potent both in the biochemical and cellular assays were discovered. Quinazoline 13a was found to be a potent JNK3 inhibitor (IC(50)=40 nM), with >500-fold selectivity over p38, and had good PK and brain penetration properties. With these properties, 13a is considered a potential candidate for in vivo evaluation.

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Practical Use of Computational Chemistry in Kinase Drug Discovery

Veal¹

2009

Kinase Inhibitor Drugs

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Design and synthesis of 2′-anilino-4,4′-bipyridines as selective inhibitors of c-Jun N-terminal kinase-3

Cited by 51 publications

References 26 publications

Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Synthesis and SAR of novel quinazolines as potent and brain-penetrant c-jun N-terminal kinase (JNK) Inhibitors

Practical Use of Computational Chemistry in Kinase Drug Discovery

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