含硼药物的研究进展

杜丰华; 董正川; 陈乐园; 侯文彬; 李祎亮

doi:10.11665/j.issn.1000-5048.20221101002

含硼药物的研究进展

1.
天津中医药大学，天津 301617
2.
天津红日药业股份有限公司，天津 301700
3.
中国医学科学院北京协和医学院放射医学研究所，天津市放射医学与分子核医学重点实验室，天津 300192

基金项目: 国家自然科学基金青年项目资助（No.82104012）；中国医学科学院医学与健康科技创新工程重大协同创新项目资助（No.2021-I2M-1-042）

计量
- 文章访问数: 0442
- HTML全文浏览量: 0
- PDF下载量: 0861
出版历程
- 收稿日期: 2022-10-31
- 修回日期: 2023-03-14
- 刊出日期: 2023-04-24

Research progress of boron-containing drugs

1.
Tianjin University of Traditional Chinese Medicine, Tianjin 301617
2.
Tianjin Chase Sun Pharmaceutical Co., Ltd., Tianjin 301700
3.
Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Radiation Medicine, Tianjin Municipal Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin 300192, China

Funds: This study was supported by the Youth Project of National Natural Science Foundation of China (No.82104012); and the Major Collaborative Innovation Project of Medical and Health Science and Technology Innovation Project of the Chinese Academy of Medical Sciences (No.2021-I2M-1-042)

摘要

摘要: 近年来，关于含硼药物，尤其是硼酸类药物的研究逐渐增多。含硼药物代表了药物化学家在研发领域开拓的一类新成果，这类药物在抗炎、抗菌、抗肿瘤等方面正扮演着愈发重要的角色。目前，全球已有5个含硼药物获批上市，正处于临床试验阶段的含硼药物也不在少数，同时近几年在研新药的不断出现，极大地扩展了硼在药物研发领域的应用。本文通过介绍硼元素的特性，并对处于各个研究阶段的代表性含硼药物的适应证，与靶点的结合机制，以及它们进入临床试验后的进展进行综述，以期为含硼药物的进一步研究提供参考。
- 含硼化合物 /
- 上市药物 /
- 共价抑制 /
- 药物靶标 /
- 临床试验
Abstract: In recent years, the research on boron-containing drugs, especially boric acid drugs, has been increasing gradually.Boron-containing drugs, which have been a new area of research for pharmaceutical chemists in the development of new drugs, play an increasingly important anti-inflammatory, antibacterial, and anti-tumor role.At present, five boron-containing drugs have been approved, many are under clinical trials, and more are under investigation around the world, which has greatly expanded the application of boron in the research of new drugs.This paper introduces the characteristics of boron, and reviews the indications of representative boron-containing drugs in various research stages, their binding mechanisms with targets, and their progress after entering clinical trials, aiming to provide reference for further research on boron-containing drugs.
- boron-containing compound /
- approved drug /
- covalent inhibition /
- drug target /
- clinical trial

HTML全文

参考文献(78)

[1]	Wiskur SL, Lavigne JJ, Ait-Haddou H, et al. pKa values and geometries of secondary and tertiary amines complexed to boronic acids implications for sensor design[J]. Org Lett, 2001, 3(9): 1311-1314.
[2]	Springsteen G, Wang BH. A detailed examination of boronic acid-diol complexation[J]. Tetrahedron, 2002, 58(26): 5291-5300.
[3]	Paramore A, Frantz S. Bortezomib[J]. Nat Rev Drug Discov 2,003, 2(8): 611-612.
[4]	Chen D, Frezza M, Schmitt S, et al. Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives[J]. Curr Cancer Drug Targets, 2011, 11(3): 239-253.
[5]	Adams J, Behnke M, Chen SW, et al. Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids[J]. Bioorg Med Chem Lett, 1998, 8(4): 333-338.
[6]	Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates[J]. Chem Biol, 2001, 8(8): 739-758.
[7]	Groll M, Berkers CR, Ploegh HL, et al. Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome[J]. Structure, 2006, 14(3): 451-456.
[8]	Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents[J]. Cancer Res, 1999, 59(11):2615-2622.
[9]	Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells[J]. Cancer Res, 2001, 61(7): 3071-3076.
[10]	Shirley M. Ixazomib: first global approval[J]. Drugs, 2016, 76(3): 405-411.
[11]	Kupperman E, Lee EC, Cao YY, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer[J]. Cancer Res, 2010, 70(5): 1970-1980.
[12]	Muz B, Ghazarian RN, Ou M, et al. Spotlight on ixazomib: potential in the treatment of multiple myeloma[J]. Drug Des Devel Ther, 2016, 10: 217-226.
[13]	Chauhan D, Tian Z, Zhou B, et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells[J]. Clin Cancer Res, 2011, 17(16): 5311-5321.
[14]	Markham A. Tavaborole: first global approval[J]. Drugs, 2014, 74(13): 1555-1558.
[15]	Jinna S, Finch J. Spotlight on tavaborole for the treatment of onychomycosis[J]. Drug Des Devel Ther, 2015, 9: 6185-6190.
[16]	Rock FL, Mao WM, Yaremchuk A, et al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site[J]. Science, 2007, 316(5832): 1759-1761.
[17]	Baker SJ, Zhang YK, Akama T, et al. Discovery of a new boron-containing antifungal agent, 5-fluoro-1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole (AN₂₆₉₀), for the potential treatment of onychomycosis[J]. J Med Chem, 2006, 49(15):4447-4450.
[18]	Benkovic SJ, Baker SJ, Alley MRK, et al. Identification of borinic esters as inhibitors of bacterial cell growth and bacterial methyltransferases, CcrM and MenH[J]. J Med Chem, 2005, 48(23):7468-7476.
[19]	Markinson B, Ghannoum M, Winter T, et al. Examining the benefits of the boron-based mechanism of action and physicochemical properties of tavaborole in the treatment of onychomycosis[J]. J Am Podiatr Med Assoc, 2018, 108(1):12-19.
[20]	Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies[J]. J Am Acad Dermatol, 2015, 73(1): 62-69.
[21]	Milakovic M, Gooderham MJ. Phosphodiesterase-4 inhibition in psoriasis[J]. Psoriasis (Auckl), 2021, 11: 21-29.
[22]	Tulsian NK, Krishnamurthy S, Anand GS. Channeling of cAMP in PDE-PKA complexes promotes signal adaptation[J]. Biophys J, 2017, 112(12): 2552-2566.
[23]	Fleming YM, Frame MC, Houslay MD. PDE4-regulated cAMP degradation controls the assembly of integrin-dependent actin adhesion structures and REF52 cell migration[J]. J Cell Sci, 2004, 117(Pt 11): 2377-2388.
[24]	Grewe SR, Chan SC, Hanifin JM. Elevated leukocyte cyclic AMP—phosphodiesterase in atopic disease: a possible mechanism for cyclic AMP—agonist hyporesponsiveness[J]. J Allergy Clin Immunol, 1982, 70(6): 452-457.
[25]	Zane LT, Chanda S, Jarnagin K, et al. Crisaborole and its potential role in treating atopic dermatitis: overview of early clinical studies[J]. Immunotherapy, 2016, 8(8): 853-866.
[26]	Hanifin JM, Chan SC, Cheng JB, et al. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis[J]. J Investig Dermatol, 1996, 107(1): 51-56.
[27]	Akama T, Baker SJ, Zhang YK, et al. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN₂₇₂₈) for the potential topical treatment of psoriasis and atopic dermatitis[J]. Bioorg Med Chem Lett, 2009, 19(8): 2129-2132.
[28]	Jarnagin K, Chanda S, Coronado D, et al. Crisaborole topical ointment, 2%: a nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis[J]. J Drugs Dermatol, 2016, 15(4): 390-396.
[29]	Zane LT, Kircik L, Call R, et al. Crisaborole topical ointment, 2% in patients ages 2 to 17 years with atopic dermatitis: a phase 1b, open-label, maximal-use systemic exposure study[J]. Pediatr Dermatol, 2016, 33(4): 380-387.
[30]	Murrell DF, Gebauer K, Spelman L, et al. Crisaborole topical ointment, 2% in adults with atopic dermatitis: a phase 2a, vehicle-controlled, proof-of-concept study[J]. J Drugs Dermatol, 2015, 14(10): 1108-1112.
[31]	Tom WL, Van Syoc M, Chanda S, et al. Pharmacokinetic profile, safety, and tolerability of crisaborole topical ointment, 2% in adolescents with atopic dermatitis: an open-label phase 2a study[J]. Pediatr Dermatol, 2016, 33(2): 150-159.
[32]	Stein Gold LF, Spelman L, Spellman MC, et al. A phase 2, randomized, controlled, dose-ranging study evaluating crisaborole topical ointment, 0.5% and 2% in adolescents with mild to moderate atopic dermatitis[J]. J Drugs Dermatol, 2015, 14(12):1394-1399.
[33]	Geng B, Hebert AA, Takiya L, et al. Efficacy and safety trends with continuous, long-term crisaborole use in patients Aged ≥ 2 years with mild-to-moderate atopic dermatitis[J]. Dermatol Ther (Heidelb), 2021, 11(5): 1667-1678.
[34]	Andrei S, Valeanu L, Chirvasuta R, et al. New FDA approved antibacterial drugs: 2015-2017[J]. Discoveries (Craiova), 2018, 6(1): e81.
[35]	Lee YM, Kim J, Trinh S. Meropenem-vaborbactam (vabomere^TM): another option for carbapenem-resistant Enterobacteriaceae[J]. P T, 2019, 44(3): 110-113.
[36]	Zhou JY, Stapleton P, Haider S, et al. Boronic acid inhibitors of the class A β-lactamase KPC-2[J]. Bioorg Med Chem, 2018, 26(11): 2921-2927.
[37]	Hecker SJ, Reddy KR, Totrov M, et al. Discovery of a cyclic boronic acid β-lactamase inhibitor (RPX7009) with utility vs class A serine carbapenemases[J]. J Med Chem, 2015, 58(9): 3682-3692.
[38]	Lomovskaya O, Sun DX, Rubio-Aparicio D, et al. Vaborbactam: spectrum of beta-lactamase inhibition and impact of resistance mechanisms on activity in Enterobacteriaceae[J]. Antimicrob Agents Chemother, 2017, 61(11): e01443-e01417.
[39]	Baldwin CM, Lyseng-Williamson KA, Keam SJ. Meropenem: a review of its use in the treatment of serious bacterial infections[J]. Drugs, 2008, 68(6): 803-838.
[40]	Wenzler E, Scoble PJ. An appraisal of the pharmacokinetic and pharmacodynamic properties of meropenem-vaborbactam[J]. Infect Dis Ther, 2020, 9(4): 769-784.
[41]	Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial[J]. JAMA, 2018, 319(8): 788-799.
[42]	O''Farrell AM, van Vliet A, Abou Farha K, et al. Pharmacokinetic and pharmacodynamic assessments of the dipeptidyl peptidase-4 inhibitor PHX1149: double-blind, placebo-controlled, single- and multiple-dose studies in healthy subjects[J]. Clin Ther, 2007, 29(8): 1692-1705.
[43]	Johnson KMS. Dutogliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus[J]. Curr Opin Investig Drugs, 2010, 11(4):455-463.
[44]	Gupta R, Walunj SS, Tokala RK, et al. Emerging drug candidates of dipeptidyl peptidase IV (DPP IV) inhibitor class for the treatment of type 2 diabetes[J]. Curr Drug Targets, 2009, 10(1): 71-87.
[45]	Garcia-Soria G, Gonzalez-Galvez G, Argoud GM, et al. The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus[J]. Diabetes Obes Metab, 2008, 10(4): 293-300.
[46]	von Lewinski D, Selvanayagam JB, Schatz RA, et al. "Protocol for a phase 2, randomized, double-blind, placebo-controlled, safety and efficacy study of dutogliptin in combination with filgrastim in early recovery post-myocardial infarction": study protocol for a randomized controlled trial[J]. Trials, 2020, 21(1): 744.
[47]	Baker CH, Welburn SC. The long wait for a new drug for human African trypanosomiasis[J]. Trends Parasitol, 2018, 34(10): 818-827.
[48]	Jacobs RT, Nare B, Wring SA, et al. SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis[J]. PLoS Negl Trop Dis, 2011, 5(6): e1151.
[49]	Wall RJ, Rico E, Lukac l, et al. Clinical and veterinary trypanocidal benzoxaboroles target CPSF₃[J]. Proc Natl Acad Sci U S A, 2018, 115(38): 9616-9621.
[50]	U. S. National Library of Meidcine. Safety and tolerability study of acoziborole in g-HAT seropositive subjects (OXA004). (2022-01-25)[2022-09-28]https://www.clinicaltrials.gov/ct2/show/NCT05256017.
[51]	Li XF, Hernandez V, Rock FL, et al. Discovery of a potent and specific M. tuberculosis leucyl-tRNA synthetase inhibitor: (S)-3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy) benzo[c][1,2] oxaborol-1(3H)-ol (GSK656)[J]. J Med Chem, 2017, 60(19): 8011-8026.
[52]	Wei YY, Yang F, Tang J, et al. Advances in the research of anti-tuberculosis drugs[J]. J China Pharm Univ (中国药科大学学报), 2020, 51(2): 231-239.
[53]	Tenero D, Derimanov G, Carlton A, et al. First-time-in-human study and prediction of early bactericidal activity for GSK3036656, a potent leucyl-tRNA synthetase inhibitor for tuberculosis treatment[J]. Antimicrob Agents Chemother, 2019, 63(8):e00240-e00219.
[54]	U. S. National Library of Meidcine. An early bactericidal activity, safety and tolerability of GSK3036656 in subjects with drug-sensitive pulmonary tuberculosis[EB/OL]. (2018-06-15)[2022-01-03]. https://www.clinicaltrials.gov/ct2/show/NCT03557281.
[55]	Arama T, Plattner J, Kimura R, et al. Structure-activity studies led to the discovery of AN2898 in development for topical treatment of psoriasis and atopic dermatitis[J]. J Am Acad Dermatol, 2009, 60(3): AB71.
[56]	Xiao YC, Yu JL, Dai QQ, et al. Targeting metalloenzymes by boron-containing metal-binding pharmacophores[J]. J Med Chem, 2021, 64(24): 17706-17727.
[57]	Lee ZE, Gogoleva T, Heerinckx F, et al. AN2728 and AN2898 ointments demonstrate safety and efficacy in a bilateral study of atopic dermatitis[J]. J Dermatol Sci, 2013, 69(2): e34.
[58]	Krajnc A, Brem J, Hinchliffe P, et al. Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamases[J]. J Med Chem, 2019, 62(18): 8544-8556.
[59]	Liu B, Trout REL, Chu GH, et al. Discovery of taniborbactam (VNRX-5133): a broad-spectrum serine- and metallo-β-lactamase inhibitor for carbapenem-resistant bacterial infections[J]. J Med Chem, 2020, 63(6): 2789-2801.
[60]	Dowell JA, Dickerson D, Henkel T. Safety and pharmacokinetics in human volunteers of taniborbactam (VNRX-5133), a novel intravenous β-lactamase inhibitor[J]. Antimicrob Agents Chemother, 2021, 65(11): e0105321.
[61]	U. S. National Library of Meidcine. Safety and efficacy study of cefepime/VNRX-5133 in patients with complicated urinary tract infections (CERTAIN-1)[EB/OL]. (2019-01-15)[2021-12-23]. https://www.clinicaltrials.gov/ct2/show/NCT03840148.
[62]	Chong PY, Shotwell JB, Miller J, et al. Design of n-benzoxaborole benzofuran GSK8175-optimization of human pharmacokinetics inspired by metabolites of a failed clinical HCV inhibitor[J]. J Med Chem, 2019, 62(7): 3254-3267.
[63]	Deng YL, Campbell F, Han KL, et al. Randomized clinical trials towards a single-visit cure for chronic hepatitis C: oral GSK2878175 and injectable RG-101 in chronic hepatitis C patients and long-acting injectable GSK2878175 in healthy participants[J]. J Viral Hepat, 2020, 27(7): 699-708.
[64]	Tsivkovski R, Totrov M, Lomovskaya O. Biochemical characterization of QPX7728, a new ultrabroad-spectrum beta-lactamase inhibitor of serine and metallo-beta-lactamases[J]. Antimicrob Agents Chemother, 2020, 64(6): e00130-e00120.
[65]	Hecker SJ, Reddy KR, Lomovskaya O, et al. Discovery of cyclic boronic acid QPX7728, an ultrabroad-spectrum inhibitor of serine and metallo-β-lactamases[J]. J Med Chem, 2020, 63(14): 7491-7507.
[66]	Lomovskaya O, Rubio-Aparicio D, Nelson K, et al. In vitro activity of the ultrabroad-spectrum beta-lactamase inhibitor QPX7728 in combination with multiple beta-lactam antibiotics against Pseudomonas aeruginosa[J]. Antimicrob Agents Chemother, 2021, 65(6): e00210-e00221.
[67]	U. S. National Library of Meidcine. P1 Single and multiple ascending dose (SAD/MAD) study of IV QPX7728 alone and combined with QPX2014 in NHV [EB/OL]. (2020-05-08)[2022-10-10] https://www.clinicaltrials.gov/ct2/show/NCT04380207.
[68]	Adams S, Miller GT, Jesson MI, et al. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism[J]. Cancer Res, 2004, 64(15): 5471-5480.
[69]	Lankas GR, Leiting B, Roy RS, et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9[J]. Diabetes, 2005, 54(10): 2988-2994.
[70]	Strohbach JW, Akama T, Blakemore DC, et al. Boron containing PDE4 inhibitors: US20200108083[P]. 2020-04-09.
[71]	Klein M, Busch M, Friese-Hamim M, et al. Structure-based optimization and discovery of M3258, a specific inhibitor of the immunoproteasome subunit LMP7 (β5i)[J]. J Med Chem, 2021, 64(14): 10230-10245.
[72]	Zhang J, Zhang JY, Hao GY, et al. Design, synthesis, and structure-activity relationship of 7-propanamide benzoxaboroles as potent anticancer agents[J]. J Med Chem, 2019, 62(14): 6765-6784.
[73]	Wang YL, Liu S, Yu ZJ, et al. Structure-based development of (1-(3''-mercaptopropanamido) methyl) boronic acid derived broad-spectrum, dual-action inhibitors of metallo- and serine-β-lactamases[J]. J Med Chem, 2019, 62(15): 7160-7184.
[74]	Ju Y, He LH, Zhou YZ, et al. Discovery of novel peptidomimetic boronate ClpP inhibitors with noncanonical enzyme mechanism as potent virulence blockers in vitro and in vivo[J]. J Med Chem, 2020, 63(6): 3104-3119.
[75]	Zhang YK, Plattner JJ, Easom EE, et al. Benzoxaborole antimalarial agents. part 5. lead optimization of novel amide pyrazinyloxy benzoxaboroles and identification of a preclinical candidate[J]. J Med Chem, 2017, 60(13): 5889-5908.
[76]	Tan J, Grouleff JJ, Jitkova Y, et al. De novo design of boron-based peptidomimetics as potent inhibitors of human ClpP in the presence of human ClpX[J]. J Med Chem, 2019, 62(13): 6377-6390.
[77]	Clark JM, Salgado-Polo F, MacDonald SJF, et al. Structure-based design of a novel class of autotaxin inhibitors based on endogenous allosteric modulators[J]. J Med Chem, 2022, 65(8): 6338-6351.
[78]	Mowbray CE, Braillard S, Glossop PA, et al. DNDI-6148: a novel benzoxaborole preclinical candidate for the treatment of visceral leishmaniasis[J]. J Med Chem, 2021, 64(21): 16159-16176.