Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design, Synthesis, and Evaluation of Isoquinoline Ureas as TRPV1 Antagonists

Author(s): Nehaben A. Gujarati, Bradley J. Undem and Vijaya L. Korlipara*

Volume 16, Issue 2, 2020

Page: [202 - 211] Pages: 10

DOI: 10.2174/1573406415666190626130453

Price: $65

Abstract

Background: The inhibition of transient receptor potential vanilloid receptor 1 (TRPV1) has emerged as a novel approach for the treatment of various pain states. Pyrrolidinyl urea, SB 705498 with pKb = 7.3 in guinea pig TRPV1 receptor has been investigated in Phase II clinical trials for pain and chronic cough. Another heteroaryl urea derivative, A-425619 1, has been reported to be a potent and selective TRPV1 antagonist of capsaicin-evoked receptor activation with an IC50 value of 4 nM in hTRPV1.

Objective: A series of thirteen A-425619 1 analogues with modifications centered around the Cregion were synthesized to understand the binding site characteristics of TRPV1 receptors.

Methods: We synthesized a series of isoquinoline ureas and evaluated their antagonist potency using smooth muscle assay using guinea pig trachea along with the evaluation of the molecular properties and molecular modeling using CoMFA studies.

Results: p-Chloro 4, p-bromo 5, m-isothiocyanate 15, and p-isothiocyanate 16 derivatives were found to be the most potent members of the series with pKb values in the range of 7.3-7.4 in the functional assay using guinea pig trachea. The lead compound A-425619 1 exhibited a pKb value of 8.1 in this assay.

Conclusion: The para-substituted analogues were found to be more potent than the ortho- and meta- analogues in the biological assay. This observation was further supported by molecular modeling studies using CoMFA.

Keywords: TRPV1, pain, isoquinoline ureas, A-425619, SB 705498, smooth muscle assay.

« Previous Next »
Graphical Abstract

[1]
Clapham, D.E.; Runnels, L.W.; Strübing, C. The TRP ion channel family. Nat. Rev. Neurosci., 2001, 2(6), 387-396.
[http://dx.doi.org/10.1038/35077544] [PMID: 11389472]
[2]
Messeguer, A.; Planells-Cases, R.; Ferrer-Montiel, A. Physiology and pharmacology of the vanilloid receptor. Curr. Neuropharmacol., 2006, 4(1), 1-15.
[http://dx.doi.org/10.2174/157015906775202995] [PMID: 18615132]
[3]
Bevan, S.; Quallo, T.; Andersson, D.A. Trpv1. Handb. Exp. Pharmacol., 2014, 222, 207-245.
[http://dx.doi.org/10.1007/978-3-642-54215-2_9] [PMID: 24756708]
[4]
Westaway, S.M. The potential of transient receptor potential vanilloid type 1 channel modulators for the treatment of pain. J. Med. Chem., 2007, 50(11), 2589-2596.
[http://dx.doi.org/10.1021/jm060637e] [PMID: 17489570]
[5]
Clapham, D.E. TRP channels as cellular sensors. Nature, 2003, 426(6966), 517-524.
[http://dx.doi.org/10.1038/nature02196] [PMID: 14654832]
[6]
Roberts, L.A.; Connor, M. TRPV1 antagonists as a potential treatment for hyperalgesia. Recent Patents CNS Drug Discov., 2006, 1(1), 65-76.
[http://dx.doi.org/10.2174/157488906775245309] [PMID: 18221192]
[7]
Wolkerstorfer, A.; Handler, N.; Buschmann, H. New approaches to treating pain. Bioorg. Med. Chem. Lett., 2016, 26(4), 1103-1119.
[http://dx.doi.org/10.1016/j.bmcl.2015.12.103] [PMID: 26774577]
[8]
LeGay, C.M.; Derksen, D.J. Structure-Activity Relationship (SAR) Studies of Transient Receptor Potential (TRP). Channel Modulators. Med. Chem. Rev., 2017, 52, 443-463.
[9]
Walpole, C.S.J.; Bevan, S.; Bovermann, G.; Boelsterli, J.J.; Breckenridge, R.; Davies, J.W.; Hughes, G.A.; James, I.; Oberer, L.; Winter, J. The discovery of capsazepine, the first competitive antagonist of the sensory neuron excitants capsaicin and resiniferatoxin. J. Med. Chem., 1994, 37(13), 1942-1954.
[http://dx.doi.org/10.1021/jm00039a006] [PMID: 8027976]
[10]
Szallasi, A.; Cortright, D.N.; Blum, C.A.; Eid, S.R. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat. Rev. Drug Discov., 2007, 6(5), 357-372.
[http://dx.doi.org/10.1038/nrd2280] [PMID: 17464295]
[11]
Rami, H.K.; Thompson, M.; Stemp, G.; Fell, S.; Jerman, J.C.; Stevens, A.J.; Smart, D.; Sargent, B.; Sanderson, D.; Randall, A.D.; Gunthorpe, M.J.; Davis, J.B. Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorg. Med. Chem. Lett., 2006, 16(12), 3287-3291.
[http://dx.doi.org/10.1016/j.bmcl.2006.03.030] [PMID: 16580202]
[12]
Korlipara, V.L. Transient receptor potential vanilloid 1 channel modulation: a novel approach to pain therapy. Curr. Bioact. Compd., 2008, 4, 110-125.
[http://dx.doi.org/10.2174/157340708785294235]
[13]
Jetter, M.C.; Youngman, M.A.; McNally, J.J.; Zhang, S-P.; Dubin, A.E.; Nasser, N.; Dax, S.L. N-isoquinolin-5-yl-N'-aralkyl-urea and -amide antagonists of human vanilloid receptor 1. Bioorg. Med. Chem. Lett., 2004, 14(12), 3053-3056.
[PMID: 15149643]
[14]
Park, H-G.; Choi, J-Y.; Choi, S-H.; Park, M-K.; Lee, J.; Suh, Y-G.; Cho, H.; Oh, U.; Kim, H-D.; Joo, Y-H.; Lee, J.; Kim, S-Y.; Park, Y-H.; Jeong, Y.S.; Choi, J.K.; Kim, J.K.; Kang, S-U.; Jew, S-S. N-4-Methansulfonamidobenzyl-N′-2-substituted 4-tert-butyl-benzyl thioureas as potent vanilloid receptor antagonistic ligands. Bioorg. Med. Chem. Lett., 2004, 14, 1693-1696.
[15]
Perner, R.J.; DiDomenico, S.; Koenig, J.R.; Gomtsyan, A.; Bayburt, E.K.; Schmidt, R.G.; Drizin, I.; Zheng, G.Z.; Turner, S.C.; Jinkerson, T.; Brown, B.S.; Keddy, R.G.; Lukin, K.; McDonald, H.A.; Honore, P.; Mikusa, J.; Marsh, K.C.; Wetter, J.M.; George, K.S.; Jarvis, M.F.; Faltynek, C.R.; Lee, C.H. In vitro structure-activity relationship and in vivo characterization of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 antagonists. J. Med. Chem., 2007, 50(15), 3651-3660.
[http://dx.doi.org/10.1021/jm070276i] [PMID: 17583335]
[16]
ClinicalTrials.gov Identifier: NCT01424514. Available at https://clinicaltrials. gov/c t2/show/NCT2018.
[17]
ClinicalTrials.gov Identifier: NCT01476098. Available at: https://clinicaltrials. gov/ct2/show2018.
[18]
ClinicalTrials.gov Identifier: NCT01476098. Available at: 2018.
[19]
ClinicalTrials.gov Identifier: NCT01673529. Available at: https://clinicaltrials. gov/2018.
[20]
Gomtsyan, A.; Bayburt, E.K.; Schmidt, R.G.; Zheng, G.Z.; Perner, R.J.; Didomenico, S.; Koenig, J.R.; Turner, S.; Jinkerson, T.; Drizin, I.; Hannick, S.M.; Macri, B.S.; McDonald, H.A.; Honore, P.; Wismer, C.T.; Marsh, K.C.; Wetter, J.; Stewart, K.D.; Oie, T.; Jarvis, M.F.; Surowy, C.S.; Faltynek, C.R.; Lee, C.H. Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain: structure-activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties. J. Med. Chem., 2005, 48(3), 744-752.
[http://dx.doi.org/10.1021/jm0492958] [PMID: 15689158]
[21]
Bellamy, F.D.; Ou, K. Selective reduction of aromatic nitro compounds with stannous chloride in non acidic and non aqueous medium. Tetrahedron Lett., 1984, 25, 839-842.
[http://dx.doi.org/10.1016/S0040-4039(01)80041-1]
[22]
Korlipara, V.L.; Takemori, A.E.; Portoghese, P.S. Electrophilic N-benzylnaltrindoles as δ opioid receptor-selective antagonists. J. Med. Chem., 1995, 38(8), 1337-1343.
[http://dx.doi.org/10.1021/jm00008a012] [PMID: 7731019]
[23]
Drizin, I.; Gomtsyan, A.; Bayburt, E.K.; Schmidt, R.G.; Zheng, G.Z.; Perner, R.J.; DiDomenico, S.; Koenig, J.R.; Turner, S.C.; Jinkerson, T.K.; Brown, B.S.; Keddy, R.G.; McDonald, H.A.; Honore, P.; Wismer, C.T.; Marsh, K.C.; Wetter, J.M.; Polakowski, J.S.; Segreti, J.A.; Jarvis, M.F.; Faltynek, C.R.; Lee, C.H. Structure-activity studies of a novel series of 5,6-fused heteroaromatic ureas as TRPV1 antagonists. Bioorg. Med. Chem., 2006, 14(14), 4740-4749.
[http://dx.doi.org/10.1016/j.bmc.2006.03.027] [PMID: 16621571]
[24]
Ellis, J.L.; Undem, B.J. Inhibition by capsazepine of resiniferatoxin- and capsaicin-induced contractions of guinea pig trachea. J. Pharmacol. Exp. Ther., 1994, 268(1), 85-89.
[PMID: 8301598]

Rights & Permissions Print Cite
Article Metrics
16
© 2024 Bentham Science Publishers | Privacy Policy