In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease.
TRPC6
calcium
fibrosis
ion channels
nuclear factor of activated T cells
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
14 05 2019
14 05 2019
Historique:
pubmed:
28
4
2019
medline:
31
3
2020
entrez:
28
4
2019
Statut:
ppublish
Résumé
Transient receptor potential canonical type 6 (TRPC6) is a nonselective receptor-operated cation channel that regulates reactive fibrosis and growth signaling. Increased TRPC6 activity from enhanced gene expression or gain-of-function mutations contribute to cardiac and/or renal disease. Despite evidence supporting a pathophysiological role, no orally bioavailable selective TRPC6 inhibitor has yet been developed and tested in vivo in disease models. Here, we report an orally bioavailable TRPC6 antagonist (BI 749327; IC
Identifiants
pubmed: 31028142
pii: 1815354116
doi: 10.1073/pnas.1815354116
pmc: PMC6525474
doi:
Substances chimiques
TRPC6 Cation Channel
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10156-10161Subventions
Organisme : NHLBI NIH HHS
ID : R35 HL135827
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007227
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL119012
Pays : United States
Déclaration de conflit d'intérêts
Conflict of interest statement: D.M., J.F.D., L.P., D.W., G.R., S.M.W., S.Z., H.S.Q, J.J.K, A.S., and S.S.P. are full-time employees of Boehringer Ingelheim Pharmaceuticals, Inc. M.M, M.R.N, A.B., and C.S. were full-time employees of Boehringer Ingelheim Pharmaceuticals, Inc. A.B. and M.R.N. are listed as coinventors on a US provisional patent application filed by Boehringer Ingelheim Pharmaceuticals, Inc. relevant to this work. J.F.D., N.Z., D.d.C., X.Z., N.T.B., J.A.C., D.P.H., and M.M.M. were employees of Hydra Biosciences, and received options. This work was supported in part by Boehringer Ingelheim Pharmaceuticals, Inc.
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