Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration (original) (raw)
Related papers
Journal of Medicinal Chemistry, 2010
Given the significant body of data supporting an essential role for c-jun-N-terminal kinase (JNK) in neurodegenerative disorders, we set out to develop highly selective JNK inhibitors, with good cell potency, and good brain penetration properties. The structure activity relationships (SAR) around a series of aminopyrimidines was evaluated utilizing biochemical and cell-based assays to measure JNK inhibition, and brain penetration in mice. Microsomal stability in three species, P450 inhibition, inhibition of generation of reactive oxygen species (ROS), and pharmacokinetics in rats were also measured. Compounds 9g, 9i, 9j, and 9l had greater than 135-fold selectivity over p38, and cellbased IC 50 values < 100 nM. Moreover, compound 9l showed an IC 50 = 0.8 nM for inhibition of ROS and had good pharmacokinetic properties in rat, along with a brain-to-plasma ratio of 0.75. These results suggest that biaryl substituted aminopyrimidines represented by compound 9l may serve as the first small molecule inhibitors to test efficacy of JNK inhibitors in neurodegenerative disorders.
Bioorganic & medicinal …, 2005
Imidazole-based structures of p38 inhibitors served as a starting point for the design of JNK3 inhibitors. Construction of a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold led to the synthesis of the (S)-enantiomers, which exhibited p38/JNK3 IC 50 ratio of up to 10 and were up to 20 times more potent inhibitors of JNK3 than the relevant (R)-enantiomers. The JNK3 inhibitory potency correlated well with inhibition of c-Jun phosphorylation and neuroprotective properties of the compounds in low K + -induced cell death of rat cerebellar granule neurones.
Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors
Bioorganic & Medicinal Chemistry Letters, 2014
The design and synthesis of isoxazole 3 is described, a potent JNK inhibitor with two fold selectivity over p38. Optimization of this scaffold led to compounds 27 and 28 which showed greatly improved selectivity over p38 by maintaining the JNK3 potency of compound 3. Extensive SAR studies will be described as well as preliminary in vivo data of the two lead compounds.
Journal of Medicinal Chemistry, 2005
Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a critical role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of our internal compound collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivatives as potent and selective JNK1,-2,-3 inhibitors. Starting from initial hit 1 (AS007149), the chemistry and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored. Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3. Therefore, compound 6 was further optimized by exploring a number of distal combinations in place of the chlorine atom. This led to the observation that the presence of an aromatic group, two carbons away from the aminopyrimidine moiety and bearing substituents conferring hydrogen bond acceptor (HBA) properties, could improve the potency. Further improvements to the biological and biopharmaceutical profile of the most promising compounds were performed, resulting in the discovery of compound 59 (AS601245). The in vitro and in vivo anti-inflammatory potential of this new JNK inhibitor was investigated and found to demonstrate efficacy per oral route in an experimental model of rheumatoid arthritis (RA).
1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3
Bioorganic & Medicinal Chemistry Letters, 2009
A series of 1-aryl-3,4-dihydroisoquinoline inhibitors of JNK3 are described. Compounds 20 and 24 are the most potent inhibitors (pIC50 7.3 and 6.9, respectively in a radiometric filter binding assay), with 10-and 1000-fold selectivity over JNK2 and JNK1, respectively, and selectivity within the wider mitogen-activated protein kinase (MAPK) family against p38a and ERK2. X-ray crystallography of 16 reveals a highly unusual binding mode where an H-bond acceptor interaction with the hinge region is made by a chloro substituent.
JNK inhibitors: is there a future?
JNK is a subfamily of MAP kinases that hat regulates a range of biological processes implicated in response to stress, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock as well as growth factors like PDGF, EGF, FGF, etc. They were originally identified as kinases that bind and phosphorylate JUN on S63 and Se73 within its transcriptional activation domain. The deregulation of these kinases is shown to be involved in human diseases, such as cancer, immune diseases and neurodegenerative disorders. The realization of the therapeutic potential of the inhibition of JNKs led to a thorough search for small-molecule inhibitors first for research purposes, but later also for therapeutic applications. Here, we discuss some of the most well-known JNK inhibitors and their use in basic research or clinical science.