2. Academic Validation
  3. In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease

In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease

  • Proc Natl Acad Sci U S A. 2019 May 14;116(20):10156-10161. doi: 10.1073/pnas.1815354116.
Brian Leei Lin 1,  Damian Matera 2,  Julia F Doerner 3,  Nan Zheng 3,  Donato Del Camino 3,  Sumita Mishra 1,  Hong Bian 2,  Svetlana Zeveleva 2,  Xiaoguang Zhen 3,  Nathaniel T Blair 3,  Jayhong A Chong 3,  David P Hessler 3,  Djahida Bedja 1,  Guangshuo Zhu 1,  Grace K Muller 1,  Mark J Ranek 1,  Lynn Pantages 2,  Mary McFarland 2,  Matthew R Netherton 4,  Angela Berry 4,  Diane Wong 4,  Georg Rast 5,  Hu Sheng Qian 2,  Steven M Weldon 2,  Jay J Kuo 2,  Achim Sauer 5,  Chris Sarko 4,  Magdalene M Moran 3,  David A Kass 6,  Steven S Pullen 7
Affiliations

Affiliations

  • 1 Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205.
  • 2 Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.
  • 3 Hydra Biosciences, Cambridge, MA 02138.
  • 4 Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.
  • 5 Drug Discovery Sciences, Boehringer Ingelheim GmbH & Co. KG, 88397 Biberach an der Riss, Germany.
  • 6 Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205; dkass@jhmi.edu steven.pullen@boehringer-ingelheim.com.
  • 7 Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877; dkass@jhmi.edu steven.pullen@boehringer-ingelheim.com.
PMID: 31028142 DOI: 10.1073/pnas.1815354116
Abstract

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; IC50 13 nM against mouse TRPC6, t1/2 8.5-13.5 hours) with 85- and 42-fold selectivity over the most closely related channels, TRPC3 and TRPC7. TRPC6 calcium conductance results in the stimulation of nuclear factor of activated T cells (NFAT) that triggers pathological cardiac and renal fibrosis and disease. BI 749327 suppresses NFAT activation in HEK293T cells expressing wild-type or gain-of-function TRPC6 mutants (P112Q, M132T, R175Q, R895C, and R895L) and blocks associated signaling and expression of prohypertrophic genes in isolated myocytes. In vivo, BI 749327 (30 mg/kg/day, yielding unbound trough plasma concentration ∼180 nM) improves left heart function, reduces volume/mass ratio, and blunts expression of profibrotic genes and interstitial fibrosis in mice subjected to sustained pressure overload. Additionally, BI 749327 dose dependently reduces renal fibrosis and associated gene expression in mice with unilateral ureteral obstruction. These results provide in vivo evidence of therapeutic efficacy for a selective pharmacological TRPC6 inhibitor with oral bioavailability and suitable pharmacokinetics to ameliorate cardiac and renal stress-induced disease with fibrosis.

Keywords

TRPC6; calcium; fibrosis; ion channels; nuclear factor of activated T cells.

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