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DOI: 10.1055/s-0043-1775470
A Decade of FDA-Approved Pharmacophore-Based Small Molecules: Advances in Medicinal Chemistry from 2014 to 2024

Abstract
Over the past decade, the pharmaceutical field has seen significant advancements with the approval of innovative small-molecule drugs by the FDA. These low molecular weight compounds have set new benchmarks in therapy. This review examines their design, medical applications, mechanisms of action, and impact across various areas of medicine. It also emphasizes the key structural features critical to their success, highlighting progress in medicinal chemistry.
1 Introduction
2 Overview of Small Molecule Therapeutics (2014–2024)
3 Pharmacophore Classification and Key Approvals
3.1 2014: Foundational Advancements
3.2 2015–2016: Addressing Rare and Chronic Diseases
3.3 2017–2019: Oncology and Neurological Milestones
3.4 2020–2021: Responses to Global Health Needs
3.5 2022–2024: Cutting-Edge Innovations
3.6 Remdesivir; A Perfect Example of Pharmacophore-Driven Drug Discovery
4 Structural and Mechanistic Insights
4.1 Structural Determinants
4.2 Mechanistic Versatility
5 Therapeutic Breakthroughs
5.1 Oncological Innovations
5.2 Infectious Disease Management
5.3 Neurological and Psychiatric Advances
5.4 Cardiovascular and Related Advances
5.5 Miscellaneous Diseases
5.6 Summary
6 Challenges and Future Perspectives
6.1 Addressing Drug Resistance
6.2 Integrating Artificial Intelligence (AI) in Drug Discovery
6.3 Precision Medicine
6.4 Sustainability in Drug Development
7 Conclusion
Publication History
Received: 31 December 2024
Accepted after revision: 27 February 2025
Article published online:
04 June 2025
© 2025. Thieme. All rights reserved
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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References
- 1 Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC. N. Engl. J. Med. 2020; 383: 1813
- 2 Ertl P, Rohde B, Selzer P. J. Med. Chem. 2000; 43: 3714
- 3a Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Adv. Drug Delivery Rev. 2001; 46: 3
- 3b Sliwoski G, Kothiwale S, Meiler J, Lowe Jr EW. Pharmacological reviews 2013; 66(1): 334
- 4 For trends in pharmaceutical approvals, see Food and Drug Administration (FDA) (accessed Dec 23, 2024): https://www.fda.gov
- 5 Keefe LJ, Stoll VS. Drug Discovery Today 2019; 24: 377
- 6 Ferreira LL. G, Andricopulo AD. Drug Discovery Today 2019; 24: 1157
- 7a Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F. N. Engl. J. Med. 2014; 371: 2167
- 7b Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F. N. Engl. J. Med. 2015; 373: 1582
- 8 2014 FDA drug approvals: Mullard A. Nat. Rev. Drug Discovery 2015; 14: 77
- 9a 2014 in review: FDA approval of new drugs: Kinch MS. Drug Discovery Today 2017; 22: 620
- 9b Meoli A, Fainardi V, Deolmi M, Chiopris G, Marinelli F, Caminiti C, Esposito S, Pisi G. Pharmaceuticals 2021; 14(9): 928
- 10 2015 FDA drug approvals: Mullard A. Nat. Rev. Drug Discovery 2016; 15: 73
- 11 2015 in review: FDA approval of new drugs: Kinch MS. Drug Discovery Today 2016; 21: 1046
- 12 2016 FDA drug approvals: Mullard A. Nat. Rev. Drug Discovery 2017; 16: 73
- 13a Mullard A. Nat. Rev. Drug Discovery 2018; 17: 81
- 13b Mullard A. Nat. Rev. Drug Discovery 2018; 17: 150
- 14 2018 FDA drug approvals: Mullard A. Nat. Rev. Drug Discovery 2019; 18: 85
- 15 Mullard A. Nat. Rev. Drug Discovery 2020; 2019 FDA drug approvals: 19: 79
- 16 Bhutani P, Joshi G, Raja N, Bachhav N, Rajanna PK, Bhutani H, Paul AT, Kumar R. J. Med. Chem. 2021; 64: 2339
- 17 Yuan S, Luo YQ, Zuo JH, Liu H, Li F, Yu B. Eur. J. Med. Chem. 2021; 215: 113284
- 18 2020 FDA drug approvals: Mullard A. Nat. Rev. Drug Discovery 2021; 20: 85
- 19 Yuan S, Wang DS, Liu H, Zhang SN, Yang WG, Lv M, Zhou YX, Zhang SY, Song J, Liu HM. Eur. J. Med. Chem. 2023; 245: 114898
- 20 2021 FDA approvals: Mullard A. Nat. Rev. Drug Discovery 2022; 21: 83
- 21 Benedetto Tiz D, Bagnoli L, Rosati O, Marini F, Santi C, Sancineto L. Pharmaceutics 2022; 14: 2538
- 22 2022 FDA approvals: Mullard A. Nat. Rev. Drug Discovery 2023; 22: 83
- 23 Bai YR, Seng DJ, Xu Y, Zhang YD, Zhou WJ, Jia YY, Song J, He ZX, Liu HM, Yuan S. Eur. J. Med. Chem. 2024; 276: 116706
- 24 Zheng L, Wang W, Sun Q. Signal Transduction Targeted Ther. 2024; 9: 46
- 25 Novel Drug Approvals for 2024; U.S. Food and Drug Administration: USA, 2024; https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024 (accessed Dec 23, 2024)
- 26 Verdin P. Nat. Rev. Drug Discovery 2024; 23: 331
- 27 Verdin P. Nat. Rev. Drug Discovery 2024; 23: 806
- 28a Liang C, Tian L, Liu Y, Hui N, Qiao G, Li H, Shi Z, Tang Y, Zhang D, Xie X, Zhao X. Eur. J. Med. Chem. 2020; 201: 112527
- 28b Veklury (remdesivir) EUA Letter of Authorization; archived October 22, 2020.
- 29 Wang L, Rui M, Peng J, Ling Y. J. Chin. Pharm. Sci. 2024; 33: 1082
- 30 Cannalire R, Cerchia C, Beccari AR, Di Leva FS, Summa V. J. Med. Chem. 2022; 65: 2716
- 31 FDA Approves First Treatment for COVID; Food and Drug Administration (FDA): USA, 2020; https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19 (accessed Mar 2, 2025)
- 32 Jennifer Barrett. FDA Approves Remdesivir for Treatment of COVID-19. Drug Topics [Internet] 2020; Available from: https://www.drugtopics.com/view/fda-approves-remdesivir-for-treatment-of-covid-19
- 33 Kannaiyan R, Mahadevan D. Expert Rev. Anticancer Ther. 2018; 18: 1249
- 34 Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HP. V. Mol. Cancer 2018; 17: 48
- 35 Congreve M, Oswald C, Marshall FH. Trends Pharmacol. Sci. 2017; 38: 837
- 36 Batool M, Ahmad B, Choi S. Int. J. Mol. Sci. 2019; 20: 2783
- 37 Caron G, Kihlberg J, Ermondi G. Med. Res. Rev. 2019; 39: 1707
- 38 Cramer J, Sager CP, Ernst B. J. Med. Chem. 2019; 62: 8915
- 39 Ceborska M, Kędra-Królik K, Narodowiec J, Dąbrowa K. Cryst. Growth Des. 2021; 21: 6714
- 40 Agostinho DA. S, Jesus AR, Silva AB. P, Esperança JM. S. S, Paiva A, Duarte AR. C, Reis PM. J. Pharm. Sci. 2021; 110: 2489
- 41 Xie B, Liu Y, Li X, Yang P, He W. Acta Pharm. Sin. B 2024; 14: 4683
- 42 Svec A, Adameova A. Mol. Cell Biochem. 2023; 478: 1661
- 43 Jiang Y, Wang Y, Ma S, Qian L, Jing Y, Chen X, Yang J. Front. Cardiovasc. Med. 2025; 11: 1415668
- 44 Climent E, Benaiges D, Pedro-Botet J. Front. Cardiovasc. Med. 2021; 8: 687585
- 45 Han B, Salituro FG, Blanco MJ. ACS Med. Chem. Lett. 2020; 11: 1810
- 46 Slosky LM, Caron MG, Barak LS. Trends Pharmacol. Sci. 2021; 42: 283
- 47 Abbott JA, Wen H, Liu B, Gupta SS, Iacobucci GJ, Zheng W, Popescu GK. Mol. Psychiatry 2025; 30: 1009
- 48 Abdel-Magid AF. ACS Med. Chem. Lett. 2015; 6: 104
- 49 Kanes S, Colquhoun H, Gunduz-Bruce H, Raines S, Arnold R, Schacterle A, Doherty J, Epperson CN, Deligiannidis KM, Riesenberg R, Hoffmann E, Rubinow D, Jonas J, Paul S, Meltzer-Brody S. Lancet 2017; 390: 480
- 50 Cibičková L. J. Clin. Lipidol. 2011; 5: 373
- 51 Kaczorowski GJ, McManus OB, Priest BT, Garcia ML. J. Gen. Physiol. 2008; 131: 399
- 52 Bagal SK, Brown AD, Cox PJ, Omoto K, Owen RM, Pryde DC, Sidders B, Skerratt SE, Stevens EB, Storer RI, Swain NA. J. Med. Chem. 2013; 56: 593
- 53 Armijo JA, Shushtarian M, Valdizan EM, Cuadrado A, de las Cuevas I, Adín J. Curr. Pharm. Des. 2005; 11: 1975
- 54 Sher E. Expert Opin. Invest. Drugs 2004; 13: 1651
- 55 Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA. N. Engl. J. Med. 2017; 376: 629
- 56 Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS. N. Engl. J. Med. 2018; 378: 113
- 57 Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ. N. Engl. J. Med. 2015; 373: 1814
- 58 Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, Romero-Gomez M, Zarski JP, Agarwal K, Buggisch P, Foster GR, Bräu N, Buti M, Jacobson IM, Subramanian GM, Ding X, Mo H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Mangia A, Marcellin P. N. Engl. J. Med. 2014; 370: 1889
- 59 Eastman R. T., Roth J.S., Brimacombe K.R., Simeonov A., Shen M., Patnaik S., Hall M. D. Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent Sci. 2020 May 27; 6(5), 672-683. doi: 10.1021/acscentsci.0c00489. Erratum in: ACS Cent Sci. 2020 Jun 24; 6(6),1009. doi: 10.1021/acscentsci.0c00747.
- 60 Fischer WA, Eron JJ Jr, Holman W, Cohen MS, Fang L, Szewczyk LJ, Sheahan TP, Baric R, Mollan KR, Wolfe CR, Duke ER, Azizad MM, Borroto-Esoda K, Wohl DA, Coombs RW, James Loftis A, Alabanza P, Lipansky F, Painter WP. Sci. Transl. Med. 2022; 14: eabl7430
- 61 Tan X, Xu Y, Wang S, Li J, Hu C, Chen Z, Cheng Q, Wang Z. Brain Sci. 2023; 13: 1627
- 62 Edinoff AN, Akuly HA, Wagner JH, Boudreaux MA, Kaplan LA, Yusuf S, Neuchat EE, Cornett EM, Boyer AG, Kaye AM, Kaye AD. Front. Psychiatry 2021; 12: 789982
- 63 Moon SW, Kim JW, Kim DH, Adair M, Åström DO, Reines EH, Lee M, Kim G. Neuropsychiatr. Dis. Treat. 2024; 20: 2299
- 64 De Diego-Adeliño J, Crespo JM, Mora F, Neyra A, Iborra P, Gutiérrez-Rojas L, Salonia SF. Expert Opin. Drug Saf. 2022; 21: 673
- 65 Connolly KR, Thase ME. Expert Opin. Pharmacother. 2016; 17: 421
- 66 Kelliny M, Croarkin PE, Moore KM, Bobo WV. Ther. Clin. Risk Manage. 2015; 11: 1193
- 67 Mathews M, Gommoll C, Chen D, Nunez R, Khan A. Int. Clin. Psychopharmacol. 2015; 30: 67
- 68 Zhang XF, Wu L, Wan DJ, Liu RZ, Dong Z, Chen M, Yu SY. Neuropsychiatr. Dis. Treat. 2015; 11: 1957
- 69 Tomlinson B, Patil NG, Fok M, Lam CW. K. Endocrinol. Metab. 2021; 36: 279
- 70 Xu J, Shapiro MD. US Cardiol. Rev. 2021; 15: e01
- 71 Das US, Paul A, Banerjee S. Egypt Heart J. 2021; 73: 93
- 72 Packer M. Eur. Heart J. 2020; 41: 2393
- 73 Mok TS, Wu Y.-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA. N. Engl. J. Med. 2017; 376: 629
- 74 Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Nat. Rev. Cancer 2013; 13: 714
- 75 Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin SF, Kingsbury Z, Wong AS, Marass F, Humphray S, Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, Rosenfeld N. Nature 2013; 497: 108
- 76 Ventola CL. Pharm. Ther. 2015; 40: 277
- 77 Chen H, Engkvist O, Wang Y, Olivecrona M, Blaschke T. Drug Discovery Today 2018; 23: 1241
- 78 Bhati M, Virmani T, Kumar G, Sharma A, Chitranshi N. Deep Learning in Drug Discovery . In Deep Learning in Personalized Healthcare and Decision Support . Garg H, Chatterjee JM. Elsevier Academic Press; London: 2023: 263-276
- 79 Segler MH. S, Preuss M, Waller MP. Nature 2018; 555: 604
- 80 Franczyk B, Rysz J, Gluba-Brzózka A. Genes 2022; 13: 311
- 81 Johnson JA. Pharmacogenomics 2013; 14: 835
- 82 Talebi Z, Sparreboom A, Colace SI. Methods Mol. Biol. 2022; 2547: 47
- 83 Barlati S, Minelli A, Nibbio G, Bertoni L, Necchini N, Paolini S, Muscarella A, Ubertino UB, Calzavara-Pinton I, Vita A, Gennarelli M. Front. Psychiatry 2023; 14: 1307473
- 84 Corponi F, Fabbri C, Serretti A. Psychiatry Investig. 2019; 16: 645
- 85 Clark JH. Green Chem. 1999; 1: 1
- 86 Poliakoff M, Licence P. Nature 2007; 450: 810
- 87 Panda KC, Kumar R, Sahoo BM, Sruti J. Green Chemistry and Sustainable Practices . In Innovations in Chemistry, Chap 1. Abuthahir SS. S, Arockiaraj SP. Chyren Publisher; Palwal: 2024: 1-14
- 88 Rathi P, Nausheen S. Nisha, Int. J. Sci. Res. Arch. 2023; 8 (02) 161
- 89 Ozawa S, Shankar R, Leopold C, Orubu S. Health Policy Plann. 2019; 34 (Suppl. 03) iii1
- 90 Asadi-Lari M, Ahmadi Teymourlouy A, Maleki M, Afshari M. BMC Health Serv. Res. 2021; 21: 1193
Erratum:
2017 FDA drug approvals:
Erratum