Abstract
Most of modern innovative drug compounds are not the new molecular structures, but modified analogs of already known structures. The most successful chemotypes have been in operation for decades, while the structural transformations used in the design of analogues in many cases make it possible to obtain improved versions of precursor compounds. This paper analyzes innovative drug developments approved by leading national regulatory agencies. Both individual transformations in medicinal compounds approved in 2022–2023 and anthologies of a number of popular structural series of medicinal analogues are considered, and approaches to their medical and chemical design are analyzed.
REFERENCES
Zefirova, O.N., Balakin, K.V., Krasavin, M.Yu., Palyulin, V.A., Poroykov, V.V., Radchenko, E.V., Salakhutdinov, N.F., Spasov, A.A., Fisenko, V.P., and Bachurin, S.O., Izv. Akad. Nauk, Ser. Khim., 2019, no. 12, p. 2381.
Fischer, J., and Ganellin, C.R., Analogue-Based Drug Discovery, Weinheim: Wiley-VCH, 2006. https://doi.org/10.1002/3527608001
Dangi, M., Khichi, A., Jakhar, R., and Chhillar, A.K., Curr. Pharm. Biotechnol., 2021, vol. 22, p. 1030. https://doi.org/10.2174/1389201021666200908121409
Xie, Y., Yin, W., Zhang, Y., Shang, W., Wang, Z., Luan, X., Tian, G., Aisa, H.A., Xu, Y., Xiao, G., Li, J., Jiang, H., Zhang, S., Zhang, L., Xu, H.E., and Shen, J., Cell. Res., 2021, vol. 31, p. 1212. https://doi.org/10.1038/s41422-021-00570-1
Zhu, K.-W., ACS Pharmacol. Transl. Sci., 2023, vol. 6, no. 11, p. 1306. https://doi.org/10.1021/acsptsci.3c00134
Chen, X., Huang, X., Ma, Q., Kuzmič, P., Zhou, B., Xu, J., Liu, B., Jiang, H., Zhang, W., Yang, C., Wu, S., Huang, J., Li, H., Long, C., Zhao, X., Xu, H., Sheng, Y., Guo, Y., Niu, C., Xue, L., Xu, Y., Liu, J., Zhang, T., Spencer, J., Deng, W., Chen, S.-H., Xiong, X., Yang, Z., and Zhong, N., BioRxiv., 2023. https://doi.org/10.1101/2023.03.09.531862
Brown, D.G., J. Med. Chem., 2023, vol. 66, no. 11, p. 7101. https://doi.org/10.1021/acs.jmedchem.3c00521
Wermuth, C.G., The Practice of Medicinal Chemistry, Illkirch: Academic Press, 2008. https://doi.org/10.1016/B978-0-12-374194-3.X0001-7
Sun, H., Tawa, G., and Wallqvist, A., Drug. Discov. Today, 2012, vol. 17, p. 310. https://doi.org/10.1016/j.drudis.2011.10.024
Patrick, G.L., An Introduction to Medicinal Chemistry, Oxford: Oxford University Press, 2013
Mullard, A., Nat. Rev. Drug Discov., 2022, vol. 21, p. 623. https://doi.org/10.1038/d41573-022-00139-6
Chandra Mouli, H.M., Vinod, A., Kumari, S., Tiwari, A.K., Kathiravan, M.K., Ravichandiran, V., and Peraman, R., Bioorg. Chem., 2023, vol. 135. https://doi.org/10.1016/j.bioorg.2023.106490
Belete, T.M., Drug. Des. Devel. Ther., 2022, vol. 16, p. 3465. https://doi.org/10.2147/DDDT.S379496
Gillis, E.P., Eastman, K.J., Hill, M.D., Donnelly, D.J., and Meanwell, N.A., J. Med. Chem., 2015, vol. 58, p. 59. https://doi.org/10.1021/acs.jmedchem.5b00258
Meanwell, N.A., J. Med. Chem., 2018, vol. 61, p. 5822. https://doi.org/10.1021/acs.jmedchem.7b01788
Zhang, C., Ye, F., Wang, J., He, P., Lei, M., Huang, L., Huang, A., Tang, P., Lin, H., Liao, Y., Liang, Y., Ni, J., and Yan, P., J. Med. Chem., 2020, vol. 63, p. 7108. https://doi.org/10.1021/acs.jmedchem.0c00374
Burger, A., Prog. Drug. Res., 1991, vol. 37, p. 287. https://doi.org/10.1007/978-3-0348-7139-6_7
Patani, G.A. and LaVoie, E.J., Chem. Rev., 1996, vol. 96, p. 3147. https://doi.org/10.1021/cr950066q
Jayashree, B.S., Nikhil, P.S., and Paul, S., Med. Chem., 2022, vol. 18, p. 915. https://doi.org/10.2174/1573406418666220127124228
Subbaiah, M. and Meanwell, N.A., J. Med. Chem., 2021, vol. 64. N. 16, p. 14046. https://doi.org/10.1021/acs.jmedchem.1c01215
Gu, S.X., Lu, H.H., Liu, G.Y., Ju, X.L., and Zhu, Y.Y., Eur. J. Med. Chem., 2018, vol. 158, p. 371. https://doi.org/10.1016/j.ejmech.2018.09.013
Tang, K., Wang, S., Gao, W., Song, Y., and Yu, B., Acta Pharm. Sin. B, 2022, vol. 12, p. 4309. https://doi.org/10.1016/j.apsb.2022.09.022
Garcia Jimenez, D., Poongavanam, V., and Kihlberg, J., J. Med. Chem., 2023, vol. 66, p. 5377. https://doi.org/10.1021/acs.jmedchem.3c00134
Lawson, A.D.G., MacCoss, M., and Heer, J.P., J. Med. Chem., 2018, vol. 61, no. 10, p. 4283. https://doi.org/10.1021/acs.jmedchem.7b01120
Fang, Z., Song, Y., Zhan, P., Zhang, Q., and Liu, X., Future Med. Chem., 2014, vol. 6, no. 8, p. 885. https://doi.org/10.4155/fmc.14.50
Toenjes, S.T. and Gustafson, J.L., Future Med. Chem., 2018, vol. 10, p. 409. https://doi.org/10.4155/fmc-2017-0152
Perreault, S., Chandrasekhar, J., and Patel, L., Acc. Chem. Res., 2022, vol. 55, no. 18, p. 2581. https://doi.org/10.1021/acs.accounts.2c00485
Blair, H.A., Drugs, 2021, vol. 81, no. 13, p. 1573. https://doi.org/10.1007/s40265-021-01574-2
Hu, Y., Stumpfe, D., and Bajorath, J., J. Med. Chem., 2017, vol. 60, no. 4, p. 1238. https://doi.org/10.1021/acs.jmedchem.6b01437
Griesenauer, R.H., Schillebeeckx, C., and Kinch, M.S., Drug Discov. Today, 2019, vol 24, no. 4, p. 1010-1016. https://doi.org/10.1016/j.drudis.2019.01.010
Markham, A., Drugs, 2022, vol. 82, no. 5, p. 601. https://doi.org/10.1007/s40265-022-01699-y
Preskorn, S.H., J. Psychiatr. Pract., 2022, vol. 28, no. 6, p. 478. https://doi.org/10.1097/PRA.0000000000000672
Liang, C., Yuan, X., Shen, Z., Wang, Y., and Ding, L., Mol. Ther. Oncolytics., 2022, vol. 24, p. 577. https://doi.org/10.1016/j.omto.2022.01.001
St. Onge, E. and Phillips, B., J. Pharm. Technol., 2023, vol. 39, no. 3, p. 139. https://doi.org/10.1177/87551225231166531
Zhou, S., Xie, L., Zhou, C., Wang, L., Chen, J., Ding, S., Zhu, B., Su, M., and Shao, F., Clin. Transl. Sci., 2023. https://doi.org/10.1111/cts.13598
Cahn, A., Cernea, S., and Raz, I., Exp. Opin. Emerg. Drugs., 2016, vol. 21, no. 4, p. 409. https://doi.org/10.1080/14728214.2016.1257608
Kurkin, D.V, Bakulin, D.A., Morkovin, E.I., Strygin, A.V., Gorbunova, Yu.V., Volotova, E.V., Makarenko, I.I, Saparova, V.B., Drai, R.V., and Petrov, V.I., Pharmacy & Pharmacology, 2023, vol. 11, no. 1, p. 19. https://doi.org/10.19163/2307-9266-2023-11-1-19-47
Huang, W.S., Liu, S., Zou, D., Thomas, M., Wang, Y., Zhou, T., Romero, J., Kohlmann, A., Li, F., Qi, J., Cai, L., Dwight, T.A., Xu, Y., Xu, R., Dodd, R., Toms, A., Parillon, L., Lu, X., Anjum, R., Zhang, S., Wang, F., Keats, J., Wardwell, S.D., Ning, Y., Xu, Q., Moran, L.E., Mohemmad, Q.K., Jang, H.G., Clackson, T., Narasimhan, N.I., Rivera, V.M., Zhu, X., Dalgarno, D., and Shakespeare, W.C., J. Med. Chem., 2016, vol. 59, no. 10, p. 4948. https://doi.org/10.1021/acs.jmedchem.6b00306
Yang, Y., Zheng, Q., Wang, X., Zhao, S., Huang, W., Jia, L., Ma, C., Liu, S., Zhang, Y., Xin, Q., Sun, Y., and Zheng, S., Invest. New Drugs, 2023, vol. 41, no. 2, p. 254. https://doi.org/10.1007/s10637-023-01350-x
Shi, Y., Chen, J., Zhang, H., Zhang, Z., Zhang, Y., Wang, Z., Zhang, S., Zhao, J., Liu, C., Wang, X., Zhao, Y., Hu, C., Yang, L., Hao, X., Wang, L., Liu, Y., Yu, Y., Zhao, J., Wang, M., Zhang, L., Sun, S., Hu, Y., Gu, K., Hang, X., Shan, J., Zhang, Y., Tan, B., Yang, W., Yang, R., Si, M., Geng, H., Li, H., and Kang, X., BMC Med., 2023, vol. 21, no. 1, p. 72. https://doi.org/10.1186/s12916-023-02738-5
Owen, D.R., Allerton, C.M.N., Anderson, A.S., Aschenbrenner, L., Avery, M., Berritt, S., Boras, B., Cardin, R.D., Carlo, A., Coffman, K.J., Dantonio, A., Di, L., Eng, H., Ferre, R., Gajiwala, K.S., Gibson, S.A., Greasley, S.E., Hurst, B.L., Kadar, E.P., Kalgutkar, A.S., Lee, J.C., Lee, J., Liu, W., Mason, S.W., Noell, S., Novak, J.J., Obach, R.S., Ogilvie, K., Patel, N.C., Pettersson, M., Rai, D.K., Reese, M.R., Sammons, M.F., Sathish, J.G., Singh, R.S.P., Steppan, C.M., Stewart, A.E., Tuttle, J.B., Updyke, L., Verhoest, P.R., Wei, L., Yang, Q., and Zhu, Y., Science, 2021, vol. 374, p. 1586. https://doi.org/10.1126/science.abl4784
Hung, Y.P., Lee, J.C., Chiu, C.W., Lee, C.C., Tsai, P.J., Hsu, I.L., and Ko, W.C., Antibiotics (Basel), 2022, vol. 11, no. 2, p. 220. https://doi.org/10.3390/antibiotics11020220
Zhu, K.-W., ACS Pharmacol. Transl. Sci., 2023, vol. 6, no. 9, p. 1306. https://doi.org/10.1021/acsptsci.3c00134
Chen, X., Huang, X., Ma, Q., Kuzmič, P., Zhou, B., Xu, J., Liu, B., Jiang, H., Zhang, W., Yang, C., Wu, S., Huang, J., Li, H., Long, C., Zhao, X., Xu, H., Sheng, Y., Guo, Y., Niu, C., Xue, L., Xu, Y., Liu, J., Zhang, T., Spencer, J., Deng, W., Chen, S.-H., Xiong, X., Yang, Z., and Zhong, N., BioRxiv., 2023. https://doi.org/10.1101/2023.03.09.531862
Eastman, R.T., Roth, J.S., Brimacombe, K.R., Simeonov, A., Shen, M., Patnaik, S., and Hall, M.D., ACS Cent Sci., 2020, vol. 6, no. 5, p. 672. https://doi.org/10.1021/acscentsci.0c00489
Qian, H.J., Wang, Y., Zhang, M.Q., Xie, Y.C., Wu, Q.Q., Liang, L.Y., Cao, Y., Duan, H.Q., Tian, G.H., Ma, J., Zhang, Z.B., Li, N., Jia, J.Y., Zhang, J., Aisa, H.A., Shen, J.S., Yu, C., Jiang, H.L., Zhang, W.H., Wang, Z., and Liu, G.Y., Acta Pharmacol. Sin., 2022, vol. 43, no. 12, p. 313. https://doi.org/10.1038/s41401-022-00895-6
De, S.K., Curr. Med. Chem., 2023, vol. 30, no. 37, p. 4170. https://doi.org/10.2174/0929867330666230220130024
Syed, Y.Y., Drugs, 2023, vol. 83, no. 6, p. 563. https://doi.org/10.1007/s40265-023-01864-x
Lau, S.C.M. and Ou, S.I., J. Thorac. Oncol., 2022, vol. 17, no. 10, p. 1144. https://doi.org/10.1016/j.jtho.2022.08.016
Markham, A., Drugs, 2021, vol. 81, no. 17, p., 2069. https://doi.org/10.1007/s40265-021-01632-9
Shah, M., Nunes, M.R., and Stearns, V., Oncology (Williston Park), 2018, vol. 32, no. 5, p. 216.
Long, F., He, Y., Fu, H., Li, Y., Bao, X., Wang, Q., Wang, Y., Xie, C., and Lou, L., Cancer Sci., 2019, vol. 110, no. 4, p. 1420. https://doi.org/10.1111/cas.13957
Dhillon, S., Drugs, 2021, vol. 81, no. 7, p. 867. https://doi.org/10.1007/s40265-021-01508-y
Huang, L., Guo, Z., Wang, F., and Fu, L., Signal Transduct. Target Ther., 2021, vol. 6, p. 386. https://doi.org/10.1038/s41392-021-00780-4
Dhillon, S., Drugs, 2023, vol. 83, no. 3, p. 275. https://doi.org/10.1007/s40265-023-01839-y
Cascetta, P., Marinello, A., Lazzari, C., Gregorc, V., Planchard, D., Bianco, R., Normanno, N., and Morabito, A., Cancers (Basel), 2022, vol. 14, no. 21, p. 5430. https://doi.org/10.3390/cancers14215430
Xu, J., Lim, N.K., Timmerman, J.C., Shen, J., Clagg, K., Orcel, U., Bigler, R., Trachsel, E., Meier, R., White, N.A., Burkhard, J.A., Sirois, L.E., Tian, Q., Angelaud, R., Bachmann, S., Zhang, H., and Gosselin, F., Org. Lett., 2023, vol. 25, no. 19, p. 3417. https://doi.org/10.1021/acs.orglett.3c00961
Usman, M.S., Siddiqi, T.J., Memon, M.M., Khan, M.S., Rawasia, W.F., Talha Ayub, M., Sreenivasan, J., and Golzar, Y., Eur. J. Prev. Cardiol., 2018, vol. 25, no. 5, p. 495. https://doi.org/10.1177/2047487318755531
Weng, J., Zeng, L., Zhang, Y., Qu, S., Wang, X., Li, P., Fu, L., Ma, B., Ye, S., Sun, J., Lu, W., Liu, Z., Chen, D., Cheng, Z., Liu, H., Zhang, T., and Zou, J., Diabetes Obes. Metab., 2021, vol. 23, no. 8, p. 1754. https://doi.org/10.1111/dom.14389
Cefalo, C.M.A., Cinti, F., Moffa, S., Impronta, F., Sorice, G.P., Mezza, T., Pontecorvi, A., and Giaccari, A., Cardiovasc Diabetol., 2019, vol. 18, no. 1, p., 20. https://doi.org/10.1186/s12933-019-0828-y
Pałasz, A., Cież, D., Trzewik, B., Miszczak, K., Tynor, G., and Bazan, B., Top Curr. Chem. (Cham), 2019, vol. 377, no. 4, p. 19. https://doi.org/10.1007/s41061-019-0243-6
Strand, D.S., Kim, D., and Peura, D.A., Gut Liver., 2017, vol. 11, no. 1, p. 27. https://doi.org/10.5009/gnl15502
Shu, X., Zhu, Z., Fu, Y., Zhang, Z., Wang, J., Li, X., He, S., Fan, H., Liu, S., Zhang, G., Tang, J., Huang, C., Du, Q., Wang, X., Xu, B., Du, Y., Chen, Q., Wang, B., Chen,, Y., Duan, X., Xie, Y., Huo, L., Hou, X., and Lu, N., Front Med. (Lausanne), 2021, vol. 8, p. 690995. https://doi.org/10.3389/fmed.2021.690995
Wallmark, B., Scand. J. Gastroenterol. Suppl., 1986, vol. 118, p. 11. https://doi.org/10.3109/00365528609090881
Zhu, H., Pan, X., Zhang, L., Sun, H., Fan, H., Pan, Z., Huang, C., Shi, Z., Ding, J., Wang, Q., Du, Y., Lyu, N., and Li, Z., Chin. Med. J. (Engl.), 2022, vol. 135, no. 24, p. 2941. https://doi.org/10.1097/CM9.0000000000002508
Fermaglich, L.J. and Miller, K.L., Orphanet. J. Rare Dis., 2023, vol. 18, no. 163. https://doi.org/10.1186/s13023-023-02790-7
Lee, E.Y. and Shen, H.C., Biomark. Med., 2015, vol. 9, no. 1, p. 67. https://doi.org/10.2217/bmm.14.98
Schaefer, D. and Cheng, X., Pharmaceuticals (Basel), 2023, vol. 16, no. 5, p. 663. https://doi.org/10.3390/ph16050663
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The author expresses gratitude to his colleagues from the Laboratory of Medical Equipment and in vitro Diagnostics of MIPT for their assistance in preparing the text.
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Balakin, K.V. Analysis of the Structural Transformations Underlying the Design of Innovative Next-in-Class Drugs. Russ J Gen Chem 93 (Suppl 2), S401–S425 (2023). https://doi.org/10.1134/S107036322315001X
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DOI: https://doi.org/10.1134/S107036322315001X