Research Advancements on Fluorinated and Non-Fluorinated 4- Phenyl(thio)ureido-Substituted 2,2-Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants.
[en] AIMS: The present study aimed at characterizing the impact of the presence or absence of fluorine atoms on the phenyl and benzopyran rings of 4-phenyl(thio)ureido-substituted 2,2- dimethylchromans on their ability to inhibit insulin release from pancreatic β-cells or to relax vascular smooth muscle cells.
METHODS: Most compounds were found to inhibit insulin secretion and to provoke a marked myorelaxant activity.
RESULTS: The lack of a fluorine or chlorine atom at the 6-position of the 2,2-dimethylchroman core structure reduced the inhibitory activity on the pancreatic endocrine tissue. One of the most active compounds on both tissues, compound 11h (BPDZ 678), was selected for further pharmacological investigations.
CONCLUSION: The biological data suggested that 11h mainly expressed the profile of a KATP channel opener on pancreatic β-cells, although a calcium entry blockade effect was also observed. On vascular smooth muscle cells, 11h behaved as a calcium entry blocker.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Pirotte, Bernard ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Florence, Xavier ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique ; Laboratoire de Physiologie et Pharmacologie, Université Libre de Bruxelles, Faculté de Médecine, 808 Route de Lennik, B-1070 Bruxelles, Belgium
Goffin, Eric ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Leleux, Fabienne; Laboratoire de Physiologie et Pharmacologie, Université Libre de Bruxelles, Faculté de Médecine, 808 Route de Lennik, B-1070 Bruxelles, Belgium
Lebrun, Philippe; Laboratoire de Physiologie et Pharmacologie, Université Libre de Bruxelles, Faculté de Médecine, 808 Route de Lennik, B-1070 Bruxelles, Belgium
Language :
English
Title :
Research Advancements on Fluorinated and Non-Fluorinated 4- Phenyl(thio)ureido-Substituted 2,2-Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants.
Publication date :
2022
Journal title :
Medicinal chemistry (Shariqah (United Arab Emirates))
This study was supported in part by grants from the “National Fund for Scientific Research” (F.N.R.S., Belgium), from which P. Lebrun is a Research Director.
Zheng, Y.; Zhao, B.; Lu, C.; Lin, X.; Zheng, Z.; Su, W. Isolation, structure elucidation and apoptosis-inducing activity of new compounds from the edible fungus Lentinus striguellus. Nat. Prod. Commun., 2009, 4(4), 501-506. http://dx.doi.org/10.1177/1934578X0900400411 PMID: 19475993
Li, S.-G.; Tian, H.-Y.; Ye, W.-C.; Jiang, R.-W. Benzopyrans and furoquinoline alkaloids from Melicope pteleifolia. Biochem. Syst. Ecol., 2011, 39, 64-67. http://dx.doi.org/10.1016/j.bse.2011.01.005
Fobofou, S.A.T.; Franke, K.; Porzel, A.; Brandt, W.; Wessjohann, L.A. Tricyclic acylphloroglucinols from Hypericum lanceolatum and regioselective synthesis of selancins A and B. J. Nat. Prod., 2016, 79(4), 743-753. http://dx.doi.org/10.1021/acs.jnatprod.5b00673 PMID: 26950610
Reilly, R.M.; McDonald, H.A.; Puttfarcken, P.S.; Joshi, S.K.; Lewis, L.; Pai, M.; Franklin, P.H.; Segreti, J.A.; Neelands, T.R.; Han, P.; Chen, J.; Mantyh, P.W.; Ghilardi, J.R.; Turner, T.M.; Voight, E.A.; Daanen, J.F.; Schmidt, R.G.; Gomtsyan, A.; Kort, M.E.; Faltynek, C.R.; Kym, P.R. Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature. J. Pharmacol. Exp. Ther., 2012, 342(2), 416-428. http://dx.doi.org/10.1124/jpet.111.190314 PMID: 22570364
Hunt, K.W.; Cook, A.W.; Watts, R.J.; Clark, C.T.; Vigers, G.; Smith, D.; Metcalf, A.T.; Gunawardana, I.W.; Burkard, M.; Cox, A.A.; Geck Do, M.K.; Dutcher, D.; Thomas, A.A.; Rana, S.; Kal-lan, N.C.; DeLisle, R.K.; Rizzi, J.P.; Regal, K.; Sammond, D.; Groneberg, R.; Siu, M.; Purkey, H.; Lyssikatos, J.P.; Marlow, A.; Liu, X.; Tang, T.P. Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: From hit to lowering of Cerebrospinal Fluid (CSF) amyloid β in a higher species. J. Med. Chem., 2013, 56(8), 3379-3403. http://dx.doi.org/10.1021/jm4002154 PMID: 23537249
Dhawan, A.; Balwani, S.; Prasad, A.K.; Ghosh, B.; Parmar, V.S. Synthesis and evaluation of 2,2‐dimethylchroman derivatives as inhibitors of ICAM‐1 expression on human endothelial cells. J. Heterocycl. Chem., 2014, 51, 1712-1719. http://dx.doi.org/10.1002/jhet.1860
Wang, X.; Liu, B.; Searle, X.; Yeung, C.; Bogdan, A.; Greszler, S.; Singh, A.; Fan, Y.; Swensen, A.M.; Vortherms, T.; Balut, C.; Jia, Y.; Desino, K.; Gao, W.; Yong, H.; Tse, C.; Kym, P. Discovery of 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic Acid (ABBV/GLPG-2222), a potent Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) corrector for the treatment of cystic fibrosis. J. Med. Chem., 2018, 61, 1436-1449. http://dx.doi.org/10.1021/acs.jmedchem.7b01339 PMID: 29251932
Sebille, S.; De Tullio, P.; Boverie, S.; Antoine, M-H.; Lebrun, P.; Pirotte, B. Recent developments in the chemistry of potassium channel activators: The cromakalim analogs. Curr. Med. Chem., 2004, 11(9), 1213-1222. http://dx.doi.org/10.2174/0929867043365378 PMID: 15134515
Coghlan, M.J.; Carroll, W.A.; Gopalakrishnan, M. Recent developments in the biology and medicinal chemistry of potassium channel modulators: Update from a decade of progress. J. Med. Chem., 2001, 44(11), 1627-1653. http://dx.doi.org/10.1021/jm000484+ PMID: 11356099
Mannhold, R. KATP channel openers: Structure-activity relationships and therapeutic potential. Med. Res. Rev., 2004, 24(2), 213-266. http://dx.doi.org/10.1002/med.10060 PMID: 14705169
Mannhold, R. Structure-activity relationships of K(ATP) channel openers. Curr. Top. Med. Chem., 2006, 6(10), 1031-1047. http://dx.doi.org/10.2174/156802606777323647 PMID: 16787278
Cecchetti, V.; Tabarrini, O.; Sabatini, S. From cromakalim to different structural classes of K(ATP) channel openers. Curr. Top. Med. Chem., 2006, 6(10), 1049-1068. http://dx.doi.org/10.2174/156802606777323683 PMID: 16787279
Zhang, X.; Zhao, J.; Kang, S.; Yi, M.; You, S.; Shin, D-S.; Kim, D-K. A novel cromakalim analogue induces cell cycle arrest and apoptosis in human cervical carcinoma HeLa cells through the caspase-and mitochondria-dependent pathway. Int. J. Oncol., 2011, 39(6), 1609-1617. PMID: 21833470
Yokoshiki, H.; Sunagawa, M.; Seki, T.; Sperelakis, N. ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells. Am. J. Physiol., 1998, 274(1), C25-C37. http://dx.doi.org/10.1152/ajpcell.1998.274.1.C25 PMID: 9458709
Teramoto, N. Physiological roles of ATP-sensitive K+ channels in smooth muscle. J. Physiol., 2006, 572(Pt 3), 617-624. http://dx.doi.org/10.1113/jphysiol.2006.105973 PMID: 16484295
Cook, D.L.; Hales, C.N. Intracellular ATP directly blocks K+ channels in pancreatic B-cells. Nature, 1984, 311(5983), 271-273. http://dx.doi.org/10.1038/311271a0 PMID: 6090930
Seino, S.; Miki, T. Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog. Biophys. Mol. Biol., 2003, 81(2), 133-176. http://dx.doi.org/10.1016/S0079-6107(02)00053-6 PMID: 12565699
Tinker, A.; Aziz, Q.; Thomas, A. The role of ATP-sensitive potassium channels in cellular function and protection in the cardiovascular system. Br. J. Pharmacol., 2014, 171(1), 12-23. http://dx.doi.org/10.1111/bph.12407 PMID: 24102106
Inagaki, N.; Seino, S. ATP-sensitive potassium channels: Structures, functions, and pathophysiology. Jpn. J. Physiol., 1998, 48(6), 397-412. http://dx.doi.org/10.2170/jjphysiol.48.397 PMID: 10021494
Ashcroft, S.J. The beta-cell K(ATP) channel. J. Membr. Biol., 2000, 176(3), 187-206. PMID: 10931971
Sebille, S.; Gall, D.; de Tullio, P.; Florence, X.; Lebrun, P.; Pirotte, B. Design, synthesis, and pharmacological evaluation of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans: Toward tissue-selective pancreatic beta-cell KATP channel openers structurally related to (+/-)-cromakalim. J. Med. Chem., 2006, 49(15), 4690-4697. http://dx.doi.org/10.1021/jm060161z PMID: 16854075
Sebille, S.; de Tullio, P.; Florence, X.; Becker, B.; Antoine, M-H.; Michaux, C.; Wouters, J.; Pirotte, B.; Lebrun, P. New R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-benzopyrans structurally related to (+/-)-cromakalim as tissue-selective pancreatic beta-cell K(ATP) channel openers. Bioorg. Med. Chem., 2008, 16(10), 5704-5719. http://dx.doi.org/10.1016/j.bmc.2008.03.065 PMID: 18406154
Florence, X.; Sebille, S.; Tullio, Pd.; Lebrun, P.; Pirotte, B. New R/S-3,4-dihydro-2,2-dimethyl-2H-1-benzopyrans as K(ATP) channel openers: Modulation of the 4-position. Bioorg. Med. Chem., 2009, 17(22), 7723-7731. http://dx.doi.org/10.1016/j.bmc.2009.09.041 PMID: 19822435
Florence, X.; Desvaux, V.; Goffin, E.; de Tullio, P.; Pirotte, B.; Lebrun, P. Influence of the alkylsulfonylamino substituent located at the 6-position of 2,2-dimethylchromans structurally related to cromakalim: From potassium channel openers to calcium entry blockers? Eur. J. Med. Chem., 2014, 80, 36-46. http://dx.doi.org/10.1016/j.ejmech.2014.04.024 PMID: 24763361
Pirotte, B.; Florence, X.; Goffin, E.; Medeiros, M.B.; de Tullio, P.; Lebrun, P. 4-Phenylureido/thioureido-substituted 2,2-dimethylchroman analogs of cromakalim bearing a bulky ‘carbamate’ moiety at the 6-position as potent inhibitors of glucose-sensitive insulin secretion. Eur. J. Med. Chem., 2016, 121, 338-351. http://dx.doi.org/10.1016/j.ejmech.2016.05.042 PMID: 27267004
Pirotte, B.; Florence, X.; Goffin, E.; Lebrun, P. Deciphering structure-activity relationships in a series of 2,2-dimethylchromans acting as inhibitors of insulin release and smooth muscle relaxants. ChemMedChem, 2017, 12(21), 1810-1817. http://dx.doi.org/10.1002/cmdc.201700409 PMID: 28967705
Pirotte, B.; Florence, X.; Goffin, E.; Lebrun, P. 2,2-Dimethyl-3,4-dihydro-2H-1,4-benzoxazines as isosteres of 2,2-dimethylchromans acting as inhibitors of insulin release and vascular smooth muscle relaxants. MedChemComm, 2019, 10(3), 431-438. http://dx.doi.org/10.1039/C8MD00593A PMID: 31015906
Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: Looking beyond intuition. Science, 2007, 317(5846), 1881-1886. http://dx.doi.org/10.1126/science.1131943 PMID: 17901324
Swallow, S. Fluorine in medicinal chemistry. Prog. Med. Chem., 2015, 54, 65-133. http://dx.doi.org/10.1016/bs.pmch.2014.11.001 PMID: 25727703
Gillis, E.P.; Eastman, K.J.; Hill, M.D.; Donnelly, D.J.; Meanwell, N.A. Applications of fluorine in medicinal chemistry. J. Med. Chem., 2015, 58(21), 8315-8359. http://dx.doi.org/10.1021/acs.jmedchem.5b00258 PMID: 26200936
Lebrun, P.; Becker, B.; Morel, N.; Ghisdal, P.; Antoine, M-H.; de Tullio, P.; Pirotte, B. KATP channel openers: Tissue selectivity of original 3-alkylaminopyrido-and 3-alkylaminobenzothiadiazine 1,1-dioxides. Biochem. Pharmacol., 2008, 75(2), 468-475. http://dx.doi.org/10.1016/j.bcp.2007.08.032 PMID: 17920043
