Stereospecific high-affinity TRPV1 antagonists: chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues.
Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists. For further optimization of the lead compounds, a series of their amide and alpha-substituted amide surrogates were investigated and novel chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues were characterized as potent and stereospecific rTRPV1 antagonists. In particular, compounds 72 and 73 displayed high binding affinities, with K i values of 4.12 and 1.83 nM and potent antagonism with K i values of 0.58 and 5.2 nM, respectively, in rTRPV1/CHO cells. These values are comparable or more potent than those of 5-iodoRTX under the same assay conditions. A distinctive binding model that includes two hydrophobic pockets is proposed for this series of compounds based on docking studies of 57 and 72 with a homology model of the TM3/4 region of TRPV1.
Ryu
HyungChul
H
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Korea.
Jin
Mi-Kyoung
MK
Kim
Su Yeon
SY
Choi
Hyun-Kyung
HK
Kang
Sang-Uk
SU
Kang
Dong Wook
DW
Lee
Jeewoo
J
Pearce
Larry V
LV
Pavlyukovets
Vladimir A
VA
Morgan
Matthew A
MA
Tran
Richard
R
Toth
Attila
A
Lundberg
Daniel J
DJ
Blumberg
Peter M
PM
D000818:Animals; D044482:Benzeneacetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D057927:Hydrophobic and Hydrophilic Interactions; D008698:Mesylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors*
D044482:Benzeneacetamides; D008698:Mesylates; C526802:N-(2-(4-t-butylbenzyl)-3-(pivaloyloxy)propyl)-2-(3-chloro-4-(methylsulfonylamino)phenyl)propionamide; C526801:N-(2-(4-t-butylbenzyl)-3-(pivaloyloxy)propyl)-2-(3-fluoro-4-(methylsulfonylamino)phenyl)propionamide; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002118:Calcium