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Letters in Organic Chemistry

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ISSN (Print): 1570-1786
ISSN (Online): 1875-6255

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Review Article

N-Heterocycles as Privileged Scaffolds in FDA Approved Different NMEs of 2021: A Review

Author(s): Faryal Chaudhry*, Rubina Munir and Nayab Malik

Volume 20, Issue 4, 2023

Published on: 28 November, 2022

Page: [287 - 299] Pages: 13

DOI: 10.2174/1570178620666221026095145

Price: $65

Abstract

The presence of N-heterocyclic ring systems as promising features in the molecular skeleton of FDA-approved drugs, underlie the remarkable contributions of these heterocyclic nuclei in the field of medicine. Despite instability risks associated with the COVID pandemic, the US FDA approved 50 drugs (36 NMEs and 14 biological products) in the year 2021. The active ingredients of 32 drugs out of these 36 NMEs (almost 89%) contain saturated, partially unsaturated and aromatic Nheterocyclic moieties in their molecular assemblies, hence dominating the medicinal approvals. While 27 molecules (75% of these NMEs drugs) are prominent small NMEs. Herein, we have considered profiling those FDA-approved 27 small-molecule drugs which are decorated with N-heterocycles as privileged scaffolds. These drugs are grouped on the basis of a number of N-heterocycles present in their structural framework. The spectrum of these drugs in terms of their structural features and medicinal importance is summarized in this review. Also, the pertinent analyses of their drug-likeliness conferring some general pharmacokinetic principles are highlighted.

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[1]
Heravi, M.M.; Zadsirjan, V. RSC Advances, 2020, 10(72), 44247-44311.
[http://dx.doi.org/10.1039/D0RA09198G] [PMID: 35557843]
[2]
Kerru, N.; Gummidi, L.; Maddila, S.; Gangu, K.K.; Jonnalagadda, S.B. Molecules, 2020, 25(8), 1909.
[http://dx.doi.org/10.3390/molecules25081909] [PMID: 32326131]
[3]
U.S. Food and Drug Administration (FDA). Available from: https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2021
[4]
Mullard, A. Nat. Rev. Drug Discov., 2022, 21(2), 83-88.
[http://dx.doi.org/10.1038/d41573-022-00001-9] [PMID: 34983958]
[5]
Tiz, B.D.; Bagnoli, L.; Rosati, O.; Marini, F.; Sancineto, L.; Santi, C. Molecules, 2022, 27(5), 1643.
[http://dx.doi.org/10.3390/molecules27051643] [PMID: 35268744]
[6]
Pathania, S.; Singh, P.K. Expert Opin. Drug Metab. Toxicol., 2021, 17(4), 351-354.
[http://dx.doi.org/10.1080/17425255.2021.1865309] [PMID: 33320017]
[7]
Deeks, E.D. Drugs, 2021, 81(16), 1937-1944.
[http://dx.doi.org/10.1007/s40265-021-01619-6] [PMID: 34674115]
[8]
Wala, K.; Szepietowski, J.C. Pharmaceuticals (Basel), 2022, 15(8), 934.
[http://dx.doi.org/10.3390/ph15080934] [PMID: 36015082]
[9]
Jayne, D.R.W.; Bruchfeld, A.N.; Harper, L.; Schaier, M.; Venning, M.C.; Hamilton, P.; Burst, V.; Grundmann, F.; Jadoul, M.; Szombati, I.; Tesař, V.; Segelmark, M.; Potarca, A.; Schall, T.J.; Bekker, P. J. Am. Soc. Nephrol., 2017, 28(9), 2756-2767.
[http://dx.doi.org/10.1681/ASN.2016111179] [PMID: 28400446]
[10]
Jayne, D.R.W.; Merkel, P.A.; Schall, T.J.; Bekker, P. N. Engl. J. Med., 2021, 384(7), 599-609.
[http://dx.doi.org/10.1056/NEJMoa2023386] [PMID: 33596356]
[11]
Lee, A. Drugs, 2022, 82(1), 79-85.
[http://dx.doi.org/10.1007/s40265-021-01643-6] [PMID: 34826105]
[12]
Lamb, Y.N. Paediatr. Drugs, 2021, 23(4), 403-409.
[http://dx.doi.org/10.1007/s40272-021-00453-3] [PMID: 34036533]
[13]
Findling, R.L.; Candler, S.A.; Nasser, A.F.; Schwabe, S.; Yu, C.; Garcia-Olivares, J.; O’Neal, W.; Newcorn, J.H. CNS Drugs, 2021, 35(6), 643-653.
[http://dx.doi.org/10.1007/s40263-021-00825-w] [PMID: 34003459]
[14]
Shirley, M. Drugs, 2022, 82(1), 71-76.
[http://dx.doi.org/10.1007/s40265-021-01649-0] [PMID: 34813049]
[15]
Gonzales, E.; Hardikar, W.; Stormon, M.; Baker, A.; Hierro, L.; Gliwicz, D.; Lacaille, F.; Lachaux, A.; Sturm, E.; Setchell, K.D.R.; Kennedy, C.; Dorenbaum, A.; Steinmetz, J.; Desai, N.K.; Wardle, A.J.; Garner, W.; Vig, P.; Jaecklin, T.; Sokal, E.M.; Jacquemin, E. Lancet, 2021, 398(10311), 1581-1592.
[http://dx.doi.org/10.1016/S0140-6736(21)01256-3] [PMID: 34755627]
[16]
Olsson, T.; Boster, A.; Fernández, O.; Freedman, M.S.; Pozzilli, C.; Bach, D.; Berkani, O.; Mueller, M.S.; Sidorenko, T.; Radue, E.W.; Melanson, M. J. Neurol. Neurosurg. Psychiatry, 2014, 85(11), 1198-1208.
[http://dx.doi.org/10.1136/jnnp-2013-307282] [PMID: 24659797]
[17]
Baldin, E.; Lugaresi, A. Expert Opin. Pharmacother., 2020, 21(16), 1955-1964.
[http://dx.doi.org/10.1080/14656566.2020.1799977] [PMID: 32808832]
[18]
Markham, A. Drugs, 2021, 81(8), 957-962.
[http://dx.doi.org/10.1007/s40265-021-01523-z] [PMID: 33939119]
[19]
Deeks, E.D. Drugs, 2021, 81(15), 1781-1786.
[http://dx.doi.org/10.1007/s40265-021-01594-y] [PMID: 34499340]
[20]
Baumann, U.; Sturm, E.; Lacaille, F.; Gonzalès, E.; Arnell, H.; Fischler, B.; Jørgensen, M.H.; Thompson, R.J.; Mattsson, J.P.; Ekelund, M.; Lindström, E.; Gillberg, P.G.; Torfgård, K.; Soni, P.N. Clin. Res. Hepatol. Gastroenterol., 2021, 45(5), 101751.
[http://dx.doi.org/10.1016/j.clinre.2021.101751] [PMID: 34182185]
[21]
Deeks, E.D. Drugs, 2019, 79(2), 215-220.
[http://dx.doi.org/10.1007/s40265-019-1051-6] [PMID: 30635838]
[22]
Tarral, A.; Blesson, S.; Mordt, O.V.; Torreele, E.; Sassella, D.; Bray, M.A.; Hovsepian, L.; Evène, E.; Gualano, V.; Felices, M.; Strub-Wourgaft, N. Clin. Pharmacokinet., 2014, 53(6), 565-580.
[http://dx.doi.org/10.1007/s40262-014-0136-3] [PMID: 24535888]
[23]
Lindner, A.K.; Lejon, V.; Chappuis, F.; Seixas, J.; Kazumba, L.; Barrett, M.P.; Mwamba, E.; Erphas, O.; Akl, E.A.; Villanueva, G.; Berg-man, H.; Simarro, P.; Kadima Ebeja, A.; Priotto, G.; Franco, J.R. Lancet Infect. Dis., 2020, 20(2), e38-e46.
[http://dx.doi.org/10.1016/S1473-3099(19)30612-7] [PMID: 31879061]
[24]
Kang, C. Drugs, 2022, 82(3), 335-340.
[http://dx.doi.org/10.1007/s40265-022-01677-4] [PMID: 35147913]
[25]
Winston, D.J.; Young, J.A.H.; Pullarkat, V.; Papanicolaou, G.A.; Vij, R.; Vance, E.; Alangaden, G.J.; Chemaly, R.F.; Petersen, F.; Chao, N.; Klein, J.; Sprague, K.; Villano, S.A.; Boeckh, M. Blood, 2008, 111(11), 5403-5410.
[http://dx.doi.org/10.1182/blood-2007-11-121558] [PMID: 18285548]
[26]
Piret, J.; Boivin, G. Antiviral Res., 2019, 163, 91-105.
[http://dx.doi.org/10.1016/j.antiviral.2019.01.011] [PMID: 30690043]
[27]
Keam, S. J. Mol. Diagn. Ther., 2021, 25(5), 647-656.
[http://dx.doi.org/10.1007/s40291-021-00548-0] [PMID: 34292532]
[28]
Voter, A.F.; Werner, R.A.; Pienta, K.J.; Gorin, M.A.; Pomper, M.G.; Solnes, L.B.; Rowe, S.P. Expert Rev. Anticancer Ther., 2022, 22(7), 681-694.
[http://dx.doi.org/10.1080/14737140.2022.2081155] [PMID: 35603510]
[29]
Dhillon, S.; Keam, S.J. Drugs, 2021, 81(7), 857-866.
[http://dx.doi.org/10.1007/s40265-021-01504-2] [PMID: 33797740]
[30]
Burris, H.A., III; Flinn, I.W.; Patel, M.R.; Fenske, T.S.; Deng, C.; Brander, D.M.; Gutierrez, M.; Essell, J.H.; Kuhn, J.G.; Miskin, H.P.; Sportelli, P.; Weiss, M.S.; Vakkalanka, S.; Savona, M.R.; O’Connor, O.A. Lancet Oncol., 2018, 19(4), 486-496.
[http://dx.doi.org/10.1016/S1470-2045(18)30082-2] [PMID: 29475723]
[31]
Kang, C. Drugs, 2021, 81(8), 953-956.
[http://dx.doi.org/10.1007/s40265-021-01520-2] [PMID: 33909276]
[32]
Schwahn, B. Neurology, 2021, 17(2), 85-91.
[http://dx.doi.org/10.17925/USN.2021.17.2.85]
[33]
Frampton, J.E. Drugs, 2021, 81(15), 1787-1794.
[http://dx.doi.org/10.1007/s40265-021-01599-7] [PMID: 34519996]
[34]
Bakris, G.L.; Agarwal, R.; Anker, S.D.; Pitt, B.; Ruilope, L.M.; Nowack, C.; Kolkhof, P.; Ferreira, A.C.; Schloemer, P.; Filippatos, G. Am. J. Nephrol., 2019, 50(5), 333-344.
[http://dx.doi.org/10.1159/000503713] [PMID: 31655812]
[35]
Lee, A. Drugs, 2021, 81(12), 1445-1450.
[http://dx.doi.org/10.1007/s40265-021-01571-5] [PMID: 34313977]
[36]
Jallow, S.; Govender, N.P. J. Fungi (Basel), 2021, 7(3), 163.
[http://dx.doi.org/10.3390/jof7030163] [PMID: 33668824]
[37]
Azie, N.; Angulo, D.; Dehn, B.; Sobel, J.D. Expert Opin. Investig. Drugs, 2020, 29(9), 893-900.
[http://dx.doi.org/10.1080/13543784.2020.1791820] [PMID: 32746636]
[38]
Markham, A. Drugs, 2021, 81(17), 2069-2074.
[http://dx.doi.org/10.1007/s40265-021-01632-9] [PMID: 34716908]
[39]
Riely, G.J.; Neal, J.W.; Camidge, D.R.; Spira, A.I.; Piotrowska, Z.; Costa, D.B.; Tsao, A.S.; Patel, J.D.; Gadgeel, S.M.; Bazhenova, L.; Zhu, V.W.; West, H.L.; Mekhail, T.; Gentzler, R.D.; Nguyen, D.; Vincent, S.; Zhang, S.; Lin, J.; Bunn, V.; Jin, S.; Li, S.; Jänne, P.A. Cancer Discov., 2021, 11(7), 1688-1699.
[http://dx.doi.org/10.1158/2159-8290.CD-20-1598] [PMID: 33632775]
[40]
Kim, E.S. Drugs, 2017, 77(17), 1917-1923.
[http://dx.doi.org/10.1007/s40265-017-0825-y] [PMID: 28971328]
[41]
Chang, E.; Weinstock, C.; Zhang, L.; Fiero, M.H.; Zhao, M.; Zahalka, E.; Ricks, T.K.; Fourie Zirkelbach, J.; Qiu, J.; Yu, J.; Chen, X.H.; Bhatnagar, V.; Goldberg, K.B.; Tang, S.; Kluetz, P.G.; Pazdur, R.; Ibrahim, A.; Beaver, J.A.; Amiri-Kordestani, L. Clin. Cancer Res., 2022, 28(3), 441-445.
[http://dx.doi.org/10.1158/1078-0432.CCR-21-2334] [PMID: 34417198]
[42]
Kang, C. Drugs, 2021, 81(11), 1355-1360.
[http://dx.doi.org/10.1007/s40265-021-01567-1] [PMID: 34279850]
[43]
Botrus, G.; Raman, P.; Oliver, T.; Bekaii-Saab, T. Expert Opin. Investig. Drugs, 2021, 30(4), 309-316.
[http://dx.doi.org/10.1080/13543784.2021.1864320] [PMID: 33307867]
[44]
Blair, H.A. Drugs, 2021, 81(14), 1677-1682.
[http://dx.doi.org/10.1007/s40265-021-01593-z] [PMID: 34463931]
[45]
Przepiorka, D.; Le, R.Q.; Ionan, A.; Li, R.J.; Wang, Y.H.; Gudi, R.; Mitra, S.; Vallejo, J.; Okusanya, O.O.; Ma, L.; Yang, Y.; Patel, P.; Mezaache, D.; Shah, R.; Banerjee, A.; McLamore, S.; Maung, A.N.; Goldberg, K.B.; Pazdur, R.; Theoret, M.R.; De Claro, R.A. Clin. Cancer Res., 2022, 28(12), 2488-2492.
[http://dx.doi.org/10.1158/1078-0432.CCR-21-4176] [PMID: 35135839]
[46]
Markham, A.; Duggan, S. Drugs, 2021, 81(6), 721-726.
[http://dx.doi.org/10.1007/s40265-021-01496-z] [PMID: 33770393]
[47]
Armstrong, P.W.; Pieske, B.; Anstrom, K.J.; Ezekowitz, J.; Hernandez, A.F.; Butler, J.; Lam, C.S.P.; Ponikowski, P.; Voors, A.A.; Jia, G.; McNulty, S.E.; Patel, M.J.; Roessig, L.; Koglin, J.; O’Connor, C.M. N. Engl. J. Med., 2020, 382(20), 1883-1893.
[http://dx.doi.org/10.1056/NEJMoa1915928] [PMID: 32222134]
[48]
Deeks, E.D. Drugs, 2022, 82(2), 219-226.
[http://dx.doi.org/10.1007/s40265-021-01662-3] [PMID: 35041175]
[49]
Yeung, D.T.; Shanmuganathan, N.; Hughes, T.P. Blood, 2022, 139(24), 3474-3479.
[http://dx.doi.org/10.1182/blood.2021014689] [PMID: 35468180]
[50]
Réa, D.; Mauro, M.J.; Boquimpani, C.; Minami, Y.; Lomaia, E.; Voloshin, S.; Turkina, A.; Kim, D.W.; Apperley, J.F.; Abdo, A.; Fogliatto, L.M.; Kim, D.D.H.; le Coutre, P.; Saussele, S.; Annunziata, M.; Hughes, T.P.; Chaudhri, N.; Sasaki, K.; Chee, L.; García-Gutiérrez, V.; Cortes, J.E.; Aimone, P.; Allepuz, A.; Quenet, S.; Bédoucha, V.; Hochhaus, A. Blood, 2021, 138(21), 2031-2041.
[http://dx.doi.org/10.1182/blood.2020009984] [PMID: 34407542]
[51]
Markham, A. Drugs, 2020, 80(8), 829-833.
[http://dx.doi.org/10.1007/s40265-020-01317-9] [PMID: 32361823]
[52]
Mathieu, L.N.; Larkins, E.; Akinboro, O.; Roy, P.; Amatya, A.K.; Fiero, M.H.; Mishra-Kalyani, P.S.; Helms, W.S.; Myers, C.E.; Skinner, A.M.; Aungst, S.; Jin, R.; Zhao, H.; Xia, H.; Zirkelbach, J.F.; Bi, Y.; Li, Y.; Liu, J.; Grimstein, M.; Zhang, X.; Woods, S.; Reece, K.; Abu-khdeir, A.M.; Ghosh, S.; Philip, R.; Tang, S.; Goldberg, K.B.; Pazdur, R.; Beaver, J.A.; Singh, H. Clin. Cancer Res., 2022, 28(2), 249-254.
[http://dx.doi.org/10.1158/1078-0432.CCR-21-1566] [PMID: 34344795]
[53]
Dhillon, S. Drugs, 2021, 81(7), 867-874.
[http://dx.doi.org/10.1007/s40265-021-01508-y] [PMID: 33861388]
[54]
Powell, K.; Prasad, V. Transl. Oncol., 2021, 14(11), 101206.
[http://dx.doi.org/10.1016/j.tranon.2021.101206] [PMID: 34419683]
[55]
Blair, H.A. Drugs, 2021, 81(13), 1573-1579.
[http://dx.doi.org/10.1007/s40265-021-01574-2] [PMID: 34357500]
[56]
Hong, D.S.; Fakih, M.G.; Strickler, J.H.; Desai, J.; Durm, G.A.; Shapiro, G.I.; Falchook, G.S.; Price, T.J.; Sacher, A.; Denlinger, C.S.; Bang, Y.J.; Dy, G.K.; Krauss, J.C.; Kuboki, Y.; Kuo, J.C.; Coveler, A.L.; Park, K.; Kim, T.W.; Barlesi, F.; Munster, P.N.; Ramalingam, S.S.; Burns, T.F.; Meric-Bernstam, F.; Henary, H.; Ngang, J.; Ngarmchamnanrith, G.; Kim, J.; Houk, B.E.; Canon, J.; Lipford, J.R.; Friberg, G.; Lito, P.; Govindan, R.; Li, B.T. N. Engl. J. Med., 2020, 383(13), 1207-1217.
[http://dx.doi.org/10.1056/NEJMoa1917239] [PMID: 32955176]
[57]
Deeks, E.D. Drugs, 2022, 82(1), 65-70.
[http://dx.doi.org/10.1007/s40265-021-01644-5] [PMID: 34813050]
[58]
Cohen, F.; Yuan, H. Ther. Clin. Risk Manag., 2022, 18, 447-456.
[http://dx.doi.org/10.2147/TCRM.S348724] [PMID: 35493707]
[59]
Voelker, R. JAMA, 2022, 327(1), 27.
[60]
Nakai, H.; Matsumura, N. Int. J. Clin. Oncol., 2022, 27(7), 1120-1126.
[http://dx.doi.org/10.1007/s10147-022-02169-x] [PMID: 35477830]
[61]
Markham, A. Drugs, 2020, 80(9), 915-922.
[http://dx.doi.org/10.1007/s40265-020-01326-8] [PMID: 32495274]
[62]
Durham, S.H.; Chahine, E.B. Ann. Pharmacother., 2021, 55(11), 1397-1409.
[http://dx.doi.org/10.1177/1060028021995586] [PMID: 33593093]
[63]
Hughes, D.L. Org. Process Res. Dev., 2019, 23(5), 716-729.
[http://dx.doi.org/10.1021/acs.oprd.9b00031]
[64]
Mechler, K.; Banaschewski, T.; Hohmann, S.; Häge, A. Pharmacol. Ther., 2022, 230, 107940.
[http://dx.doi.org/10.1016/j.pharmthera.2021.107940] [PMID: 34174276]
[65]
Kollins, S.H.; Braeckman, R.; Guenther, S.; Barrett, A.C.; Mickle, T.C.; Oh, C.; Marraffino, A.; Cutler, A.J.; Brams, M.N. J. Child Adolesc. Psychopharmacol., 2021, 31(9), 597-609.
[http://dx.doi.org/10.1089/cap.2021.0077] [PMID: 34714120]
[66]
Young, C.A. Pharmacy Today, 2021, 27(6), 16.
[http://dx.doi.org/10.1016/j.ptdy.2021.05.005]
[67]
Paik, J. Drugs, 2021, 81(12), 1431-1436.
[http://dx.doi.org/10.1007/s40265-021-01568-0] [PMID: 34304374]
[68]
Monahan, C.; McCoy, L.; Powell, J.; Gums, J.G. Ann. Pharmacother., 2022, 56(9), 1049-1057.
[http://dx.doi.org/10.1177/10600280211070330] [PMID: 35040357]
[69]
Knopf, A. Alcohol. Drug Abuse Wkly., 2021, 33(23), 5-6.
[http://dx.doi.org/10.1002/adaw.33097]
[70]
Lipinski, C.A. J. Pharmacol. Toxicol. Methods, 2000, 44(1), 235-249.
[http://dx.doi.org/10.1016/S1056-8719(00)00107-6] [PMID: 11274893]
[71]
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. J. Comb. Chem., 1999, 1(1), 55-68.
[http://dx.doi.org/10.1021/cc9800071] [PMID: 10746014]
[72]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[73]
Egan, W.J.; Merz, K.M., Jr; Baldwin, J.J. J. Med. Chem., 2000, 43(21), 3867-3877.
[http://dx.doi.org/10.1021/jm000292e] [PMID: 11052792]
[74]
Muegge, I.; Heald, S.L.; Brittelli, D. J. Med. Chem., 2001, 44(12), 1841-1846.
[http://dx.doi.org/10.1021/jm015507e] [PMID: 11384230]
[75]
Daina, A.; Michielin, O.; Zoete, V. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28127051]
[76]
Bakchi, B.; Krishna, A.D.; Sreecharan, E.; Ganesh, V.B.J.; Niharika, M.; Maharshi, S.; Puttagunta, S.B.; Sigalapalli, D.K.; Bhandare, R.R.; Shaik, A.B. J. Mol. Struct., 2022, 1259, 132712.
[http://dx.doi.org/10.1016/j.molstruc.2022.132712]
[77]
Martin, Y.C. Quantitative Drug Design: A Critical Introduction, 2nd ed; CRC Press Taylor & Francis Group, 2010.
[http://dx.doi.org/10.1201/9781420071009]
[78]
Martin, Y.C. J. Med. Chem., 2005, 48(9), 3164-3170.
[http://dx.doi.org/10.1021/jm0492002] [PMID: 15857122]

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