药学学报, 2020, 55(9): 1983-1994
王磊, 尤启冬. 2019年首创性小分子药物研究实例浅析[J]. 药学学报, 2020, 55(9): 1983-1994.
WANG Lei, YOU Qi-dong. First-in-class small molecule drugs in 2019[J]. Acta Pharmaceutica Sinica, 2020, 55(9): 1983-1994.

王磊1,2, 尤启冬1,2
1. 中国药科大学江苏省药物分子设计与成药性优化重点实验室, 江苏 南京 210009;
2. 中国药科大学药学院, 江苏 南京 210009
关键词:    首创性药物      小分子药物      新药研发     
First-in-class small molecule drugs in 2019
WANG Lei1,2, YOU Qi-dong1,2
1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China;
2. School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
New candidate targets, biological mechanisms as well as small-molecules are significant factors in the research and development of first-in-class drugs, which is a challenging process with a large amount of time and money devoted as well as high risks. A successful first-in-class drug can not only become a new strategy for disease treatment but can also offer innovative research ideas for the design of drugs. The Food and Drug Administration (FDA) approved 48 new drugs to the market in 2019, among which small-molecule drugs still predominated, containing several first-in-class drugs. Brexanolone, for example, is the first positive modulator of GABAA receptor for the treatment of postpartum depression; Selinexor is the first small-molecule drug to treat recurrent refractory multiple myeloma by inhibiting exportin (XPO1); Tenapanor is the first sodium/proton exchanger type 3 (NHE3) inhibitor that can treat irritable bowel syndrome; Lasmiditan is the first approved agonist with selectivity for 5-HT1F, treating migraines. The research and development processes of the first-in-class drugs mentioned above are distinctive from each other with uniqueness and innovation. In this review, we briefly analyze the background and process of the research and development of three typical cases as well as their therapeutic applications in an attempt to offer some help for the future development of first-in-class drugs.
Key words:    first-in-class    small molecule drug    drug discovery   
收稿日期: 2020-04-10
DOI: 10.16438/j.0513-4870.2020-0523
通讯作者: 尤启冬,Tel:86-25-83271351,E-mail:youqd@cpu.edu.cn
Email: youqd@cpu.edu.cn
PDF(4883KB) Free
王磊  在本刊中的所有文章
尤启冬  在本刊中的所有文章

[1] Guo Z. Concise analysis for innovation of pioneering and follow-on drugs[J]. Acta Pharm Sin (药学学报), 2016, 51:1179-1184.
[2] Karyopharm Announces FDA Approval of XPOVIO™ (selinexor) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma[EB/OL]. https://investors.karyopharm.com/news-releases/news-release-details/karyopharm-announces-fda-approval-xpoviotm-selinexor-treatment.
[3] Fukuda M, Asano S, Nakamura T, et al. CRM1 is responsible for intracellular transport mediated by the nuclear export signal[J]. Nature, 1997, 390:308-311.
[4] Nguyen KT, Holloway MP, Altura RA. The CRM1 nuclear export protein in normal development and disease[J]. Int J Biochem Mol Biol, 2012, 3:137-151.
[5] Turner JG, Sullivan DM. CRM1-mediated nuclear export of proteins and drug resistance in cancer[J]. Curr Med Chem, 2008, 15:2648-2655.
[6] Tai YT, Landesman Y, Acharya C, et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma:molecular mechanisms and therapeutic implications[J]. Leukemia, 2014, 28:155-165.
[7] Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma[J]. N Engl J Med, 2019, 381:727-738.
[8] Zhong Y, El-Gamal D, Dubovsky JA, et al. Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells[J]. Leukemia, 2014, 28:1158-1163.
[9] Etchin J, Montero J, Berezovskaya A, et al. Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice[J]. Leukemia, 2016, 30:190-199.
[10] Syed YY. Selinexor:first global approval[J]. Drugs, 2019, 79:1485-1494.
[11] Neggers JE, Vercruysse T, Jacquemyn M, et al. Identifying drug-target selectivity of small-molecule CRM1/XPO1 inhibitors by CRISPR/Cas9 genome editing[J]. Chem Biol, 2015, 22:107-116.
[12] Bhatnagar B, Zhao Q, Mims AS, et al. Selinexor in combination with decitabine in patients with acute myeloid leukemia:results from a phase 1 study[J]. Leuk Lymphoma, 2020, 61:387-396.
[13] Fichna J, Wood JT, Papanastasiou M, et al. Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C:a pilot study[J]. PLoS One, 2013, 8:e85073.
[14] Yun CH, Oh S, Zizak M, et al. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein[J]. Proc Natl Acad Sci U S A, 1997, 94:3010-3015.
[15] Donowitz M, Cha B, Zachos NC, et al. NHERF family and NHE3 regulation[J]. J Physiol, 2005, 567:3-11.
[16] Donowitz M, Mohan S, Zhu CX, et al. NHE3 regulatory complexes[J]. J Exp Biol, 2009, 212:1638-1646.
[17] Honegger KJ, Capuano P, Winter C, et al. Regulation of sodium-proton exchanger isoform 3(NHE3) by PKA and exchange protein directly activated by cAMP (EPAC)[J]. Proc Natl Acad Sci U S A, 2006, 103:803-808.
[18] McCormack PL. Linaclotide:a review of its use in the treatment of irritable bowel syndrome with constipation[J]. Drugs, 2014, 74:53-60.
[19] Liem O, Mousa HM, Benninga MA, et al. Tegaserod use in children:a single-center experience[J]. J Pediatr Gastroenterol Nutr, 2008, 46:54-58.
[20] Thompson CA. Novartis suspends tegaserod sales at FDA's request[J]. Am J Health Syst Pharm, 2007, 64:1020.
[21] McKeage K, Plosker GL, Siddiqui MA. Lubiprostone[J]. Drugs, 2006, 66:873-879.
[22] Curto M, Cipolla F, Cisale GY, et al. Profiling lasmiditan as a treatment option for migraine[J]. Expert Opin Pharmacother, 2020, 21:147-153.
[23] Vila-Pueyo M. Targeted 5-HT1F therapies for migraine[J]. Neurotherapeutics, 2018, 15:291-303.
[24] Hougaard A, Tfelt-Hansen P. Review of dose-response curves for acute antimigraine drugs:triptans, 5-HT1F agonists and CGRP antagonists[J]. Expert Opin Drug Metab Toxicol, 2015, 11:1409-1418.
[25] Olesen J. 5-Hydroxyptryptamine 1F (5-HT1F) receptor agonism. A possible new treatment principle for acute migraine attacks[J]. Cephalalgia, 2010, 30:1157-1158.
[26] Mitsikostas DD, Tfelt-Hansen P. Targeting to 5-HT1F receptor subtype for migraine treatment:lessons from the past, implications for the future[J]. Cent Nerv Syst Agents Med Chem, 2012, 12:241-249.
[27] Lamb YN. Lasmiditan:first approval[J]. Drugs, 2019, 79:1989-1996.
[28] Nelson DL, Phebus LA, Johnson KW, et al. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan[J]. Cephalalgia, 2010, 30:1159-1169.
[29] Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine[J]. Brain, 2019, 142:1894-1904.
1.王磊, 姜正羽, 尤启冬.2018年首创性小分子药物研究实例浅析[J]. 药学学报, 2019,54(7): 1145-1156