7S1N

N-Aromatic-Substituted Indazole Derivatives as Brain Penetrant and Orally Bioavailable JNK3 Inhibitors

Summary for 7S1N

• Entry DOI: 10.2210/pdb7s1n/pdb
• Descriptor: Mitogen-activated protein kinase 10, 4-[5-(2-chloro-6-fluoroanilino)-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl]-N-(oxetan-3-yl)thiophene-2-carboxamide (3 entities in total)
• Functional Keywords: mapk10, jnk3, kinase inhibitor, alzheimers diseases, indazole, azaindazole, neurodegeneration, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 53107.24

Authors

Park, H. (deposition date: 2021-09-02, release date: 2021-11-03, Last modification date: 2023-10-18)

Primary citation

Feng, Y.,Park, H.,Ryu, J.C.,Yoon, S.O.
N -Aromatic-Substituted Indazole Derivatives as Brain-Penetrant and Orally Bioavailable JNK3 Inhibitors.
Acs Med.Chem.Lett., 12:1546-1552, 2021

PubMed Abstract: An indazole/aza-indazole scaffold was developed as a novel chemotype for JNK3 inhibition. Extensive structure activity relationship (SAR) studies utilizing various in vitro and in vivo assays led to potent and highly selective JNK3 inhibitors with good oral bioavailability and high brain penetration. One lead compound, , was a potent and selective JNK3 inhibitor (IC = 0.005 μM) that had significant inhibition (>80% at 1 μM) to only JNK3 and JNK2 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in the human liver microsome ( = 92 min), and was orally bioavailable and brain penetrant (brain/plasma ratio: 56%). The cocrystal structure of in human JNK3 at a 2.1 Å resolution showed that indazole or aza-indazole-based JNK3 inhibitors demonstrated a type I kinase inhibition/binding.

PubMed: 34676036
DOI: 10.1021/acsmedchemlett.1c00334

Experimental method

X-RAY DIFFRACTION (2.11 Å)