270574-03-3Relevant articles and documents
Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4
Cheung, Mui,Bao, Weike,Behm, David J.,Brooks, Carl A.,Bury, Michael J.,Dowdell, Sarah E.,Eidam, Hilary S.,Fox, Ryan M.,Goodman, Krista B.,Holt, Dennis A.,Lee, Dennis,Roethke, Theresa J.,Willette, Robert N.,Xu, Xiaoping,Ye, Guosen,Thorneloe, Kevin S.
, p. 549 - 554 (2017/05/19)
Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. Increased pulmonary vascular pressure evokes TRPV4-dependent pulmonary edema, and therefore, inhibition of TRPV4 represents a novel approach for the treatment of pulmonary edema associated with conditions such as congestive heart failure. Herein we report the discovery of an orally active, potent, and selective TRPV4 blocker, 3-(1,4′-bipiperidin-1′-ylmethyl)-7-bromo-N-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (GSK2193874, 28) after addressing an unexpected off-target cardiovascular liability observed from in vivo studies. GSK2193874 is a selective tool for elucidating TRPV4 biology both in vitro and in vivo.
Novel compounds
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, (2008/06/13)
Certain compounds of formula (I) below or a pharmaceutically acceptable salt or hydrate thereof: wherein: R1 is H or alkyl; R2 is —R8R9; R8 is a single bond or alkyl, optionally substituted one or more times by hydroxy; R9 is aryl or cycloalkyl or heteroaryl, optionally substituted one or more times by hydroxy, alkoxy, or alkoxyalkyl; R3 is H or alkyl or cycloalkyl or cycloalkylalkyl, optionally substituted one or more times by hydroxy or by one or more fluorines; R4 is —NR10R11; R10 and R11 are independently selected from H or alkyl, or R10 and R11 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring comprising 3-8 ring members, which heterocyclic ring is unsubstituted or is substituted one or more times by one or more substituents R12; R12 is oxo or —R13 R14 R15, wherein R13 is a single bond or alkyl, R14 is OC(O) or C(O)O, and R15 is H or alkyl; R5 is an alkyl, cycloalkyl, cycloalkylalkyl, aryl, or single or fused ring aromatic heterocyclic group, which group is unsubstituted or is substituted one or more times by one or more substituents selected from halo such as fluoro, alkyl or haloalkyl such as fluoroalkyl; R6 represents H or up to three substituents independently selected from the list consisting of: alkyl, alkenyl, aryl, alkoxy or a hydroxylated derivative thereof, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, alkoxycarbonyl, haloalkyl such as trifluoromethyl, acyloxy, amino, mono- or di-alkylamino, alkoxyamido, alkoxycarboxylate or an esterified derivative thereof; R7 is H or halo; a is 1-6; and any of R1, R3, R5, R8, R9, R10, R11 and R12 may optionally be substituted one or more times by halo, hydroxy, amino, cyano, nitro, carboxy or oxo; a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds and composition in medicine.
Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity and selectivity in quinoline tachykinin receptor antagonists
Blaney,Raveglia,Artico,Cavagnera,Dartois,Farina,Grugni,Gagliardi,Luttmann,Martinelli,Nadler,Parini,Petrillo,Sarau,Scheideler,Hay,Giardina
, p. 1675 - 1689 (2007/10/03)
A stepwise chemical modification from human neurokinin-3 receptor (hNK-3R)-selective antagonists to potent and combined hNK-3R and hNK-2R antagonists using the same 2-phenylquinoline template is described. Docking studies with 3-D models of the hNK-3 and
