Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent, selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6)

Motoyama, Keisuke; Nagata, Tsutomu; Kobayashi, Jun; Nakamura, A.; Miyoshi, Naoki; Kazui, Miho; Sakurai, Katsunobu; Sakakura, Tomoko

doi:10.1016/j.bmcl.2018.03.056

Cited by 21 publications

(19 citation statements)

References 20 publications

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“…Furthermore, a bicyclo[4.3.0]nonane derivative, DS88790512, has been reported to inhibit TRPC6 with an IC 50 of 11 nM. This compound only weakly inhibited hERG and hNa V 1.5 channels at high micromolar concentrations and it displayed good oral bioavailability (Motoyama et al, 2018). However, the selectivity among TRPC channels is not known and no information is available about its therapeutic potentials.…”

Section: Modulators For Pulmonary Arterial Hypertension (Pah)-pulmonarymentioning

confidence: 99%

TRPC channels: Structure, function, regulation and recent advances in small molecular probes

Wang

Cheng

Tian

et al. 2020

Pharmacology & Therapeutics

140

152

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Transient receptor potential canonical (TRPC) channels constitute a group of receptor-operated calcium-permeable nonselective cation channels of the TRP superfamily. The seven mammalian TRPC members, which can be further divided into four subgroups (TRPC1, TRPC2, TRPC4/5, and TRPC3/6/7) based on their amino acid sequences and functional similarities, contribute to a broad spectrum of cellular functions and physiological roles. Studies have revealed complexity of their regulation involving several components of the phospholipase C pathway, G i and G o proteins, and internal Ca 2+ stores. Recent advances in cryogenic electron microscopy have provided several high-resolution structures of TRPC channels. Growing evidence demonstrates the involvement of TRPC channels in diseases, particularly the link between genetic mutations of TRPC6 and familial

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Section: Modulators For Pulmonary Arterial Hypertension (Pah)-pulmonarymentioning

confidence: 99%

TRPC channels: Structure, function, regulation and recent advances in small molecular probes

Wang

Cheng

Tian

et al. 2020

Pharmacology & Therapeutics

140

152

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“…SAR7334 was recently identified as a TRPC6 antagonist with 30-and 24-fold selectivity against TRPC3 and TRPC7, respectively, but has rapid in vivo clearance (31). An analog, DS88790512, has improved pharmacokinetics, but its selectivity profile and in vivo efficacy remain unreported (32).…”

mentioning

confidence: 99%

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

Lin

Matera

Doerner³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

103

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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 50 13 nM against mouse TRPC6, t 1/2 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. TRPC6 | ion channels | calcium | nuclear factor of activated T cells | fibrosis

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“…This compound showed higher selectivity for TRPC6 over TRPC3/7 channels. In addition, another compound DS88790512, a bicyclo[4.3.0]nonane derivative, has also been demonstrated to inhibit TRPC6 with an IC 50 at 11 nM [115]. Beyond this, some compounds derived from a natural product, i.e., SH045, larixyl acetate, have also the capability to inhibit TRPC6 channels with higher selectivity over TRPC3 and TRPC7 [109,116].…”

Section: Bi 749327mentioning

confidence: 99%

Canonical Transient Receptor Potential (TRPC) Channels in Nociception and Pathological Pain

Sun

Chu

et al. 2020

Neural Plasticity

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Chronic pathological pain is one of the most intractable clinical problems faced by clinicians and can be devastating for patients. Despite much progress we have made in understanding chronic pain in the last decades, its underlying mechanisms remain elusive. It is assumed that abnormal increase of calcium levels in the cells is a key determinant in the transition from acute to chronic pain. Exploring molecular players mediating Ca2+ entry into cells and molecular mechanisms underlying activity-dependent changes in Ca2+ signaling in the somatosensory pain pathway is therefore helpful towards understanding the development of chronic, pathological pain. Canonical transient receptor potential (TRPC) channels form a subfamily of nonselective cation channels, which permit the permeability of Ca2+ and Na+ into the cells. Initiation of Ca2+ entry pathways by these channels triggers the development of many physiological and pathological functions. In this review, we will focus on the functional implication of TRPC channels in nociception with the elucidation of their role in the detection of external stimuli and nociceptive hypersensitivity.

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Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent, selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6)

Cited by 21 publications

References 20 publications

TRPC channels: Structure, function, regulation and recent advances in small molecular probes

TRPC channels: Structure, function, regulation and recent advances in small molecular probes

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

Canonical Transient Receptor Potential (TRPC) Channels in Nociception and Pathological Pain

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