Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol‐sensitiveTRPCcation channels

T Maier; M Follmann; G Hessler; H‐W Kleemann; S Hachtel; B Fuchs; N Weissmann; W Linz; T Schmidt; M Löhn; K Schroeter; L Wang; H Rütten; C Strübing

doi:10.1111/bph.13151

journal article May 19, 2015

Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol‐sensitiveTRPCcation channels

T Maier M Follmann G Hessler H‐W Kleemann S Hachtel B Fuchs N Weissmann W Linz T Schmidt M Löhn K Schroeter L Wang

H Rütten C Strübing

British Journal of Pharmacology Vol. 172 No. 14 pp. 3650-3660 · Wiley

View at Publisher Save 10.1111/bph.13151

Abstract

Background and PurposeThe cation channel transient receptor potential canonical (TRPC) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary hypertension and ischaemia reperfusion‐induced lung oedema. We set out to discover novel inhibitors ofTRPC6channels and investigate the therapeutic potential of these agents.Experimental ApproachA library of potentialTRPCchannel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellularCa2+levels. The lead compoundSAR7334 was further characterized by whole‐cell patch‐clamp techniques. The effects ofSAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemicBPwere investigated.Key ResultsSAR7334 inhibitedTRPC6,TRPC3 andTRPC7‐mediated Ca2+influx into cells withIC50s of 9.5, 282 and 226 nM, whereasTRPC4andTRPC5‐mediated Ca2+entry was not affected. Patch‐clamp experiments confirmed that the compound blockedTRPC6 currents with anIC50of 7.9 nM. Furthermore,SAR7334 suppressedTRPC6‐dependent acuteHPVin isolated perfused lungs from mice. Pharmacokinetic studies ofSAR7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short‐term study,SAR7334 did not change mean arterial pressure in spontaneously hypertensive rats (SHR).Conclusions and ImplicationsOur results confirm the role ofTRPC6channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role inBPregulation inSHR.SAR7334 is a novel, highly potent and bioavailable inhibitor ofTRPC6channels that opens new opportunities for the investigation ofTRPCchannel functionin vivo.

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References

Details

Published: May 19, 2015
Vol/Issue: 172(14)
Pages: 3650-3660
License: View

Authors

T

T Maier

Sanofi R&D Frankfurt am Main Germany

M

M Follmann

Sanofi R&D Frankfurt am Main Germany

G

G Hessler

Sanofi R&D Frankfurt am Main Germany

H

H‐W Kleemann

Sanofi R&D Frankfurt am Main Germany

S

S Hachtel

Sanofi R&D Frankfurt am Main Germany

B

B Fuchs

Excellencecluster Cardio‐Pulmonary System (ECCPS) Universities of Giessen and Marburg Lung Center (UGMLC) Member of the German Center for Lung Research (DZL) Justus‐Liebig‐University Giessen Germany

N

N Weissmann

Excellencecluster Cardio‐Pulmonary System (ECCPS) Universities of Giessen and Marburg Lung Center (UGMLC) Member of the German Center for Lung Research (DZL) Justus‐Liebig‐University Giessen Germany

W

W Linz

Sanofi R&D Frankfurt am Main Germany

T

T Schmidt

Sanofi R&D Frankfurt am Main Germany

M

M Löhn

Sanofi R&D Frankfurt am Main Germany

K

K Schroeter

Sanofi R&D Frankfurt am Main Germany

L

L Wang

Sanofi R&D Frankfurt am Main Germany

H

H Rütten

Sanofi R&D Frankfurt am Main Germany

C

C Strübing

Sanofi R&D Frankfurt am Main Germany

Cite This Article

T Maier, M Follmann, G Hessler, et al. (2015). Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol‐sensitiveTRPCcation channels. British Journal of Pharmacology, 172(14), 3650-3660. https://doi.org/10.1111/bph.13151

Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol‐sensitiveTRPCcation channels

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