Journal of Medicinal Chemistry p. 6942 - 6990 (2017)
Update date:2022-08-15
Topics:
Okawa, Tomohiro
Aramaki, Yoshio
Yamamoto, Mitsuo
Kobayashi, Toshitake
Fukumoto, Shoji
Toyoda, Yukio
Henta, Tsutomu
Hata, Akito
Ikeda, Shota
Kaneko, Manami
Hoffman, Isaac D.
Sang, Bi-Ching
Zou, Hua
Kawamoto, Tetsuji
A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.
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