6J5L

Crystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 10e

Summary for 6J5L

• Entry DOI: 10.2210/pdb6j5l/pdb
• Descriptor: High affinity nerve growth factor receptor, N-{2-[({3-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indazol-5-yl}amino)methyl]phenyl}methanesulfonamide (3 entities in total)
• Functional Keywords: transferase inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34739.19

Authors

Kensuke, A.,Kazutaka, I. (deposition date: 2019-01-11, release date: 2019-07-17, Last modification date: 2023-11-22)

Primary citation

Shirahashi, H.,Toriihara, E.,Suenaga, Y.,Yoshida, H.,Akaogi, K.,Endou, Y.,Wakabayashi, M.,Takashima, M.
The discovery of novel 3-aryl-indazole derivatives as peripherally restricted pan-Trk inhibitors for the treatment of pain.
Bioorg.Med.Chem.Lett., 29:2320-2326, 2019

PubMed Abstract: The design, synthesis, and biological evaluation of novel 3-aryl-indazole derivatives as peripherally selective pan-Trk inhibitors are described. Three strategies were used to obtain a potent compound exhibiting low central nervous system (CNS) penetration and high plasma exposure: 1) a structure-based drug design (SBDD) approach was used to improve potency; 2) a substrate for an efflux transporter for lowering brain penetration was explored; and 3) the most basic pKa (pKa-MB) value was used as an indicator to identify compounds with good membrane permeability. This enabled the identification of the peripherally targeted 17c with the potency, kinase-selectivity, and plasma exposure required to demonstrate in vivo efficacy in a Complete Freund's adjuvant (CFA)-induced thermal hypersensitivity model.

PubMed: 31235262
DOI: 10.1016/j.bmcl.2019.06.018

Experimental method

X-RAY DIFFRACTION (2.3 Å)