A series of novel indazole derivatives of Sirt 1 activator as osteogenic regulators

Masakazu Atobe; Natsumi Yamakawa; Yasuhiro Wada; Tokuhito Goto; Masashi Kawanishi; Takeshi Ito; Makoto Saito; Masahiro Takeda; Takanori Tabata; Hirokazu Arai

doi:10.1016/j.bmcl.2017.09.049

A series of novel indazole derivatives of Sirt 1 activator as osteogenic regulators

Bioorg Med Chem Lett. 2017 Nov 1;27(21):4828-4831. doi: 10.1016/j.bmcl.2017.09.049. Epub 2017 Sep 25.

Affiliations

¹ Laboratory for Medicinal Chemistry, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan. Electronic address: [email protected].
² Laboratory for Medicinal Chemistry, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
³ Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan.

PMID: 28988762
DOI: 10.1016/j.bmcl.2017.09.049

Abstract

A series of indazole derivatives were identified as Sirt 1 activators though high-throughput screening. Optimization of each substituent on the indazole ring led to the identification of compound 13. Compound 13 appeared to give the best Sirt 1 activity of the compounds tested and also showed osteogenesis activity in a cell assay. Sirt 1 activators are therefore potential candidates for the treatment of osteoporosis.

Keywords: HTS; Indazole; Osteogeneration; Osteoporosis; Sirt 1.

MeSH terms

Acetylation / drug effects
Cell Differentiation / drug effects
Cell Line
Humans
Indazoles / chemistry*
Indazoles / metabolism
Indazoles / pharmacology
Osteogenesis / drug effects
Sirtuin 1 / chemistry
Sirtuin 1 / metabolism*
Structure-Activity Relationship
Tumor Suppressor Protein p53 / metabolism

Substances

Indazoles
Tumor Suppressor Protein p53
Sirtuin 1