Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives

Zheng, Ke; Iqbal, Saba; Hernandez, Pamela; Park, HaJeung; LoGrasso, Philip V.; Feng, Yangbo

doi:10.1021/jm501256y

Cited by 50 publications

(75 citation statements)

References 60 publications

(153 reference statements)

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“…Indeed, perhaps a small amount of JNK inhibition has a large contribution to protecting the mitochondrial membrane potential. 19,26 Similar cell potency was also obtained for other lead compounds in Table 3, such as compounds 12 and 18, indicating this observation was consistent among the class.…”

Section: Acs Medicinal Chemistry Letterssupporting

confidence: 79%

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

Zheng

Park

Iqbal

et al. 2015

ACS Med. Chem. Lett.

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A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure−activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC 50 = 15 nM), had high selectivity against p38 (IC 50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 Å. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition. A s a member of the mitogen-activated protein kinase (MAPK) family, the c-Jun N-terminal kinases (JNKs) are activated (dual phosphorylation on threonine and tyrosine) via an upstream kinase signaling cascade initiated by environmental stress and culminate in effects on both nuclear and mitochondrial function. 1−3 It is well-known that there are three human JNK isoforms, JNK1, JNK2, and JNK3. 4 JNK1 and JNK2 are ubiquitously expressed in a variety of human tissues. 2,5 Recent studies showed that JNK1 and JNK2 play an important role in the development of diabetes, obesity, arthritis, cancer, and heart disease. JNK1 seems to be involved in the development of obesity induced insulin resistance, which implies inhibition of JNK1 might be an effective way of treating type-2 diabetes. 6,7 JNK2 has been implicated to play an important role in many autoimmune disorders such as rheumatoid arthritis, asthma, and cancer, as well as in a broad range of diseases with an inflammatory component. 5,8 JNK3 is primarily expressed in the central nervous system (CNS) and plays an important role in Alzheimer's disease, 9 Parkinson's disease, and stroke. 3,10,11 Therefore, JNK inhibitors may have implications in many therapeutic areas, and development of JNK inhibitors as therapeutic agents has gained considerable interest over the past few years. 12−17 Given the significant amount of evidence supporting the role of JNK3 in neurodegenerative disorders, our interest is in discovering potent, selective JNK3 inhibitors with good in vivo pharmacokinetics (PK) profiles as potential therapeutics for CNS disease. 3,10,11,18−20 The pyridopyrimidinone scaffold based compound 1 (Figure 1) was identified in our preliminary medicinal chemistry efforts as an ATP competitive pan-JNK inhibitor with an IC 50 of 58 nM against JNK3 and 18 nM over both JNK1 and JNK2. This scaffold (pyridopyrimidinone) has long been shown to be good for kinase inhibition. 21 While genetic evidence suggests that JNK1 inhibition is not required for efficacy in many CNS applications, the...

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Section: Acs Medicinal Chemistry Letterssupporting

confidence: 79%

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

Zheng

Park

Iqbal

et al. 2015

ACS Med. Chem. Lett.

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“…To assess the drugability of these bis -aryl urea based Limk inhibitors, a few potent, selective, and membrane permeable compounds were further evaluated in in vitro and in vivo drug metabolism and pharmacokinetics (DMPK) studies. 41, 46, 50, 52–55 …”

Section: Resultsmentioning

confidence: 99%

“…Detailed procedures for these assays have been described in previous publications (ref. 41–42, 46, 48–50, and 52–55 ), and were also provided in Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

Yin

Zheng²,

Eid³

et al. 2015

J. Med. Chem.

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The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity, and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (> 400-fold), potent inhibition of cofilin phosphorylation in A7r5,PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥ 80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.

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“…Analog 24 was >35-fold selective for CDK2/5 over CDK9. We also screened 24 against a panel of other kinases inhibited by analogs with the aminopyrazole core (Aurora A, 29 Aurora B, DLK/MAP3K12, ITK, 30 JAK2, 31 JNK3, 32 LRRK2, 33 P38a/MAPK14, 32 PAK1, 34 TRKA). Remarkably the IC 50 value for the entire panel was > 10μM, indicating that analog 24 was selective for CDK2, and CDK5 (Table 2).…”

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confidence: 99%

Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy

Rana¹,

Sonawane²,

Taylor³

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives

Cited by 50 publications

References 60 publications

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy

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