t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists.
A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki=0.1nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Sunho
S
Lee
Department of Pharmaceutical Science and Technology, College of Health and Medical Science, Catholic University of Deagu, Gyeongsan-si, Gyeongsangbuk-do 38430, Republic of Korea.
Dong Wook
DW
Kang
J2H Biotech, Ansan-si, Gyeonggi-do 15426, Republic of Korea.
HyungChul
H
Ryu
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Changhoon
C
Kim
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Jihyae
J
Ann
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Hobin
H
Lee
National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Eunhye
E
Kim
National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Sunhye
S
Hong
National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Sun
S
Choi
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Peter M
PM
Blumberg
Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany.
Robert
R
Frank-Foltyn
Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany.
Gregor
G
Bahrenberg
Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany.
Hannelore
H
Stockhausen
Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany.
Thomas
T
Christoph
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.
Jeewoo
J
Lee
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
D000577:Amides; D011725:Pyridines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human
Analgesic; TRPV1 antagonists; Vanilloid receptor 1