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

Abstract

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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Statistical molecular identification of kinase inhibitors to disrupt c‐Jun N‐terminal protein kinase involved in paraquat‐mediated toxicological effects

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