N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure–activity relationships in the A-region

Kim, Yong Soo; Kil, Min-Jung; Kang, Sang-Uk; Ryu, Hyung-Chul; Kim, Myeong Seop; Cho, Yongsung; Bhondwe, Rahul S.; Thorat, Shivaji A.; Sun, Wei; Liu, Keliang; Lee, Jin Hee; Choi, Sun; Pearce, Larry V.; Pavlyukovets, Vladimir A.; Morgan, Matthew A.; Tran, Richard; Lázár, József; Blumberg, Peter M.; Lee, Jeeyeon

doi:10.1016/j.bmc.2011.11.008

Cited by 12 publications

(11 citation statements)

References 19 publications

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“…Lee and co‐workers from Seoul National University published the 2‐substituted‐pyridine propanamide derivatives as TRPV1 receptor antagonists through replacement of the phenyl ring of previous N ‐4‐ tert ‐butylbenzyl‐2‐(4‐methylsulfonylaminophenyl) propanamide ( 46, hTRPV1 K i = 46.2 nM; Fig. ) with a pyridine ring . The SARs investigations of the 2‐substituent in the pyridine moiety by various groups including amino, oxy, thio, and alkyl functions designed compound 47 (Fig.…”

Section: Medicinal Chemistry Of Trpv1 Antagonistsmentioning

confidence: 99%

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

128

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Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel.

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Section: Medicinal Chemistry Of Trpv1 Antagonistsmentioning

confidence: 99%

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

128

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“…A docking study of 2 with our hTRPV1 homology model demonstrated a novel aspect of its binding to the receptor and identified crucial hydrogen bonds between the ligand and the receptor contributing to its stereospecific potency. 14 …”

Section: Introductionmentioning

confidence: 99%

“…However, none of the compounds was found to be better than 2 in terms of both binding affinity and antagonism to capsaicin activation for rTRPV1 in CHO cells. 14,16 …”

Section: Introductionmentioning

confidence: 99%

2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as Potent Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists: Structure–Activity Relationships of 2-Amino Derivatives in the N-(6-Trifluoromethylpyridin-3-ylmethyl) C-Region

et al. 2012

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A series of N-(2-amino-6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (Ki(CAP) = 0.2 nM; IC50(pH) = 6.3 nM) and was thus ca. 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice, but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region.

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“…17 As a continuing effort to investigate the SAR of TRPV1 agonists based on the A-, B- and C-regions, we have synthesized, based on our lead agonists ( 1 and 2 ), a series of TRPV1 agonists bearing amide, reverse amide and thiourea B-regions together with their corresponding α–methylated analogues in the B-region, and we have analyzed the effect of α–methylation on receptor affinity and agonist potency. We describe here the syntheses and functional TRPV1 activities of the designed ligands and the SAR analysis of the B-region.…”

Section: Introductionmentioning

confidence: 99%

The SAR analysis of TRPV1 agonists with the α-methylated B-region

Cho

Kim

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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A series of TRPV1 agonists with amide, reverse amide, and thiourea groups in the B-region and their corresponding α-methylated analogues were investigated. Whereas the α–methylation of the amide B-region enhanced the binding affinities and potencies as agonists, that of the reverse amide and thiourea led to a reduction in receptor affinity. The analysis indicated that proper hydrogen bonding as well as steric effects in the B-region are critical for receptor binding.

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N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure–activity relationships in the A-region

Cited by 12 publications

References 19 publications

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as Potent Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists: Structure–Activity Relationships of 2-Amino Derivatives in the N-(6-Trifluoromethylpyridin-3-ylmethyl) C-Region

The SAR analysis of TRPV1 agonists with the α-methylated B-region

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