1336960-13-4

GSK 2193874 is an orally active, potent and selective TRPV4 antagonist.

GSK2193874 has been used as a transient receptor potential vanilloid 4 (TRPV4) antagonist:

• to study its effects on GSK101-induced colon contractions in mice
• to study its effects on murine compact bone-derived osteoblasts(CB-OB)
• to study its effects on lung injury post-lipopolysaccharide (LPS) in mice

GSK2193874 is a very potent, specific antagonist of TRPV4 ion channels (IC50 = 50 nM). Lung edema caused by high pulmonary venous pressure (PVP) is driven by TRPV4 activity. GSK2193874 blocks TRPV4-mediated calcium influx in cells expressing native and recombinant TRPV4, and inhibits vascular permeability and lung edema in isolated rodent and canine lungs subjected to high PVP. The compound also resolves pulmonary edema in murine myocardial infarction model.

3-(1,4'-Bipiperidin-1'-ylmethyl)-7-bromo-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.5 g, 4.34 mmol) and 1-phenylcyclopropanamine (0.900 g, 5.42 mmol) were added to a 500 mL flask with HOBT (0.664 g, 4.34 mmol), EDC ( 3.74 g, 19.52 mmol), dichloromethane (45 mL) and N,N-diisopropylethylamine (7.57 mL, 43.4 mmol). The reaction mixture was heated to 60 °C and kept for 5 hours. After the reaction was completed, it was cooled to room temperature and saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) and dichloromethane (50 mL) were added. After stirring for 30 minutes, the two phases were separated and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, filtered through a phase separator, concentrated and purified by reversed-phase HPLC (Biotage, 0-100% CH3CN/water with 0.1% TFA). The fraction containing the target product was collected, transferred to a partition funnel and saturated aqueous NaHCO3 and dichloromethane were added. The organic phase was separated and the aqueous phase was extracted three more times with dichloromethane. The organic phases were combined and concentrated to give 3-(1,4'-bipiperidin-1'-ylmethyl)-7-bromo-N-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (2.5 g, 83% yield).1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.32 (d, J = 2.01 Hz , 1H), 7.95 (s, 1H), 7.80-7.90 (m, 3H), 7.69-7.76 (m, 1H), 7.67 (d, J = 8.78 Hz, 1H), 7.42-7.50 (m, 2H), 7.38 (t, J = 7.65 Hz, 2H), 7.24-7.30 (m, 1H), 3.43 (br.s. , 2H), 2.38 (d, J = 9.79 Hz, 2H), 2.24-2.35 (m, 3H), 1.94 (t, J = 10.92 Hz, 1H), 1.59 (t, J = 10.92 Hz, 2H), 1.37-1.47 (m, 5H), 1.33 (br.s., 6H), 0.89-1.03 (m, 2H). MS (m/z) 693.2 (M + H+).

Store at +4°C

[1] Patent: WO2011/119704, 2011, A1. Location in patent: Page/Page column 49
[2] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 5, p. 549 - 554