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. Author manuscript; available in PMC: 2021 Nov 1.
Published in final edited form as: Ann N Y Acad Sci. 2020 Sep 6;1480(1):73–103. doi: 10.1111/nyas.14472

Table 3.

Representative small molecule TRPV4 antagonists

Name Structure Activity Remarks Refs.
Species Selectivity Human TRPV4 IC50 value
Ruthenium red Rat, human, porcine Non-selective 14 nM A non-specific metal-derived Ca2+ ion channel blocker; known to act as a pore blocker of TRPV4 and 12 other ion channels 239, 240
HC-067047
(2-methyl-1-[3-(4-morpholinyl)propyl]-5-phenyl-N-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide)		 graphic file with name nihms-1657936-t0020.jpg Rat, mouse Selective (?) 48 nM Developed by Hydra Biosciences 239, 241
RN-1734
(2,4-dichloro-N-isopropyl-N-(2-isopropylaminoethyl)benzene sulfonamide)		 graphic file with name nihms-1657936-t0021.jpg Human, rat, mouse Selective 2.3 µM Developed by Renovis, Inc. 239
GSK2193874
(3-(1,4’-bipiperidin-1’-ylmethyl)-7-bromo-N-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide)		 graphic file with name nihms-1657936-t0022.jpg Human, mouse, rat, canine Selective 40 nM Quinolone antagonist; orally bioavailable; efficacy was demonstrated in mitigating hydrochloric acid–induced acute lung injury;
developed by GlaxoSmithKline (GSK)		 132, 144, 242
GSK2220691 graphic file with name nihms-1657936-t0023.jpg Human, rat, mouse, dog, monkey Selective 2.5 nM Ameliorated Cl2- and hydrochloric acid–induced ALI in rodent models; developed by GSK 21
GSK2337429A graphic file with name nihms-1657936-t0024.jpg Human, rat, mouse, dog, monkey Selective 6.3 nM Ameliorated chlorine gas– and hydrochloric acid–induced ALI in rodent models; developed by GSK 21
GSK2798745
(1-(((5S,7S)-3-(5-(2-hydroxypropan-2-
yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-
azaspiro[4.5]decan-7-yl)methyl)-1Hbenzo[
d]imidazole-6-carbonitrile)		 graphic file with name nihms-1657936-t0025.jpg Human, rat, mouse, dog, monkey Selective 1.8 nM Spirocarbmate antagonist of TRPV4; first TRPV4 antagonist to reach clinical trials; Currently under BARDA-funded contract to develop as a medical countermeasure against Cl2-induced ARDS; developed by GSK 145–148, 150, 151, 193
GSK3395879
(4-(((3S,4R)-1-((2-cyano-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)oxy)-2-fluorobenzonitrile)		 graphic file with name nihms-1657936-t0026.jpg Human, rat Selective 1 nM Pyrrolidine sulfonamide derivative; reduced pulmonary edema in a rat model; exhibited good oral bioavailability; developed by GSK 243
GSK3491943 graphic file with name nihms-1657936-t0027.jpg Human, rat Selective 3.2 nM Pyrrolidinesulfonamide derivative; developed by GSK 244
GSK3527497 graphic file with name nihms-1657936-t0028.jpg Human, rat Selective 12 nM Currently under BARDA-funded contract to develop as a medical countermeasure against Cl2-induced ARDS; developed by GSK 193, 245
GSK2263095 Human, mouse, rat, canine Selective 3 nM Analog of GSK2193874; developed by GSK 132