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Discovery of a Potent and Selective TRPC5 Inhibitor, Efficacious in a Focal Segmental Glomerulosclerosis Model.
Yu, Maolin; Ledeboer, Mark W; Daniels, Matthew; Malojcic, Goran; Tibbitts, Thomas T; Coeffet-Le Gal, Marie; Pan-Zhou, Xin-Ru; Westerling-Bui, Amy; Beconi, Maria; Reilly, John F; Mundel, Peter; Harmange, Jean-Christophe.
Affiliation
  • Yu M; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Ledeboer MW; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Daniels M; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Malojcic G; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Tibbitts TT; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Coeffet-Le Gal M; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Pan-Zhou XR; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Westerling-Bui A; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Beconi M; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Reilly JF; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Mundel P; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
  • Harmange JC; Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
ACS Med Chem Lett ; 10(11): 1579-1585, 2019 Nov 14.
Article in En | MEDLINE | ID: mdl-31749913
ABSTRACT
The nonselective Ca2+-permeable transient receptor potential (TRP) channels play important roles in diverse cellular processes, including actin remodeling and cell migration. TRP channel subfamily C, member 5 (TRPC5) helps regulate a tight balance of cytoskeletal dynamics in podocytes and is suggested to be involved in the pathogenesis of proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS). As such, protection of podocytes by inhibition of TRPC5 mediated Ca2+ signaling may provide a novel therapeutic approach for the treatment of proteinuric kidney diseases. Herein, we describe the identification of a novel TRPC5 inhibitor, GFB-8438, by systematic optimization of a high-throughput screening hit, pyridazinone 1. GFB-8438 protects mouse podocytes from injury induced by protamine sulfate (PS) in vitro. It is also efficacious in a hypertensive deoxycorticosterone acetate (DOCA)-salt rat model of FSGS, significantly reducing both total protein and albumin concentrations in urine.

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: ACS Med Chem Lett Year: 2019 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: ACS Med Chem Lett Year: 2019 Document type: Article Affiliation country:
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