TY - JOUR
T1 - Pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists
AU - Lee, Sunho
AU - Kim, Changhoon
AU - Ann, Jihyae
AU - Thorat, Shivaji A.
AU - Kim, Eunhye
AU - Park, Jongmi
AU - Choi, Sun
AU - Blumberg, Peter M.
AU - Frank-Foltyn, Robert
AU - Bahrenberg, Gregor
AU - Stockhausen, Hannelore
AU - Christoph, Thomas
AU - Lee, Jeewoo
N1 - Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017
Y1 - 2017
N2 - A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with Ki(CAP) = 0.1 nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.
AB - A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with Ki(CAP) = 0.1 nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.
KW - Molecular modeling
KW - TRPV1 antagonist
KW - Vanilloid receptor 1
UR - http://www.scopus.com/inward/record.url?scp=85027977731&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2017.08.020
DO - 10.1016/j.bmcl.2017.08.020
M3 - Article
C2 - 28838698
AN - SCOPUS:85027977731
SN - 0960-894X
VL - 27
SP - 4383
EP - 4388
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 18
ER -