BI-749327 (BI 749327) is a potent, selective orally bioavailable TRPC6 antagonist (blocker) with IC50 of 13/19/15 nM for mouse/human/guinea pig TRPC6, respectively.
BI-749327 displays 85-and 42-fold selectivity over the most closely related channels, TRPC3 and TRPC7, minimally inhibits TRPC5 (>700-fold selective, >500-fold TRPC6 selectivity versus human TRPM8, TRPV1, TRPA1, and Nav1.5 and >150-fold selectivity against human Kv11.1 (hERG).
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.
BI 749327 (30 mg/kg/day) improves left heart function, reduces volume/mass ratio, and blunts expression of profibrotic genes and interstitial fibrosis in mice.
BI 749327 dose dependently reduces renal fibrosis and associated gene expression in mice with unilateral ureteral obstruction.