2. Academic Validation
  3. N-Aromatic-Substituted Indazole Derivatives as Brain-Penetrant and Orally Bioavailable JNK3 Inhibitors

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

  • ACS Med Chem Lett. 2021 Sep 21;12(10):1546-1552. doi: 10.1021/acsmedchemlett.1c00334.
Yangbo Feng 1 2,  HaJeung Park 3,  Jae Cheon Ryu 4,  Sung Ok Yoon 4
Affiliations

Affiliations

  • 1 Reaction Biology Corporation, One Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
  • 2 Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
  • 3 Crystallography Core Facility, Scripps Research, 130 Scripps Way, Jupiter, Florida 33458, United States.
  • 4 Department of Biological Chemistry & Pharmacology, Ohio State University College of Medicine, Columbus, Ohio 43210, United States.
PMID: 34676036 DOI: 10.1021/acsmedchemlett.1c00334
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, 29, was a potent and selective JNK3 Inhibitor (IC50 = 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 (t 1/2 = 92 min), and was orally bioavailable and brain penetrant (brain/plasma ratio: 56%). The cocrystal structure of 29 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.

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