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.