Synthesis and SAR of 4-substituted-2-aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors

Synthesis, Biological Evaluation, X-ray Structure, and Pharmacokinetics of Aminopyrimidine c-jun-N-terminal Kinase (JNK) Inhibitors

“…doses ≥ 60 mg/kg 22, 23. More recently, aminopyrimidines similar in structure to those presented in our current work have been reported for peripheral applications such as inflammatory disorders18 and type II diabetes mellitus 19. In the study by Alam et al, the key selectivity struggle was versus cyclin-dependent-kinase-2 (CDK2), where phenyl-substituted pyrazolopyridines were single digit nanomolar JNK 2, and JNK3 inhibitors showing no inhibition of CDK2 up to 10 μM 18.…”

“…From a chemistry perspective, numerous JNK selective inhibitors have begun to emerge and include compounds from classes such as indazoles 10, 11, aminopyrazoles11, aminopyridines12, 13, pyridine carboxamides13, 14, benzothien-2-yl-amides and benzothiazol-2-yl acetonitriles 15, 16, quinoline derivatives17, and aminopyrimidines 18, 19. For a recent review of all these classes see LoGrasso and Kamenecka 20.…”

Structural Basis and Biological Consequences for JNK2/3 Isoform Selective Aminopyrazoles

“…The c-jun NH 2 -terminal kinases (JNKs) are members of the mitogen-activated protein (MAP) kinase family, a group of serine/threonine kinases receiving interest over the past two decades as compelling evidence has implicated them in many diseases such as Parkinson's disease (PD) 1 2 3 4 5 6 , Alzheimer's disease (AD) 7 8 9 , diabetes 10 11 12 , and cardiovascular disease 13 14 15 16 . Because of this, numerous medicinal chemistry efforts have been initiated and selective JNK inhibitors have begun to emerge and include compounds from classes such as indazoles 17 18 , aminopyrazoles 18 , aminopyridines 19 20 , pyridine carboxamides 20 21 , benzothien-2-yl-amides and benzothiazol-2-yl acetonitriles 22 23 , quinoline derivatives 24 , and aminopyrimidines 25 26 27 . For a review of all these classes see LoGrasso and Kamenecka 28 .…”

Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors

“…37 While 2-amino-4-(hetero)aryl pyrimidine compounds are widely described in the literature, their pyridine equivalents are far less investigated, both synthetically and biologically. We anticipated to discover molecules with promising biological properties and yet patentable by replacing the pyrimidine- by a pyridine core.…”

“…We have not yet extensively explored the aniline portion of the molecule. Published data of JNK inhibitors containing the 2-aminopyrimidine or 2-aminopyridine motif 35, 37, 53 suggest that a variety of different groups will be tolerated in the 2-position. Modifications in this part of the molecule may allow to modulate the physicochemical properties and thus potentially to improve the in vivo properties and cellular potency.…”