酰胺电子等排体在先导化合物优化中的应用

doi:10.7536/PC160414

化学进展 ›› 2016, Vol. 28 ›› Issue (9) :1406-1416 DOI: 10.7536/PC160414

综述与评论

扫码查看或转发全文

酰胺电子等排体在先导化合物优化中的应用

作者信息 +

Application of Amide Bioisosteres in the Optimization of Lead Compounds

Mei Yicheng, Yang Baowei*

Author information +

文章历史 +

摘要

生物电子等排体是指一类化合物或基团，这类物质拥有近似的分子形状和体积，类似的电子分布，并由此表现出相似的物理特性。作为激动剂或拮抗剂生物电子等排体能对相同的生化相关体系发挥作用，产生彼此互相相关的生物特性。药物结构中酰胺结构作为药效团和药物的重要组成部分被广泛应用。然而作为药物分子结构的重要组成部分，酰胺结构也存在着一些明显的缺点，包括代谢不稳定、代谢产物有毒和膜渗透性差等。为了克服这些缺点同时又想保持部分酰胺的特性，生物电子等排体替换是有效的方法之一。在先导化合物的优化过程中，通过酰胺生物电子等排体替换还能达到提高生物活性和靶点选择性、降低合成难度、扩展或突破知识产权限制等目的。本综述着重介绍了近五年来酰胺及其生物电子等排体在先导化合物优化过程中的应用。希望能对含有酰胺结构的先导化合物的优化提供新的思路，加速新药研发进程。

Abstract

Bioisosteres are a class of compounds or groups,these compounds with similar molecular shapes or volume, similar electronic distribution, and similar physical properties. Bioisosteres play a role in the same related biochemical system as agonist or antagonist, which possessed in related biological activities. The amide structure can be an important part of drugs and a constituent of a pharmacophore. However, the presence of this moiety can also be responsible for some significant drawbacks about drug molecular, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes. To avoid some of these shortcomings while retaining the desired attributes of the amide moiety, bioisosteric replacement of the amide moiety in lead compounds is an effective method. Through the amide bioisosteric replacements, other aims would be goal such as increasing the target potency and selectivity, developing new structures to expand or break through the patents and decreasing the difficulty of the synthesis of the compounds. This review focuses on the application of the replacement between amide and amide bioisosteres in the optimization of lead compounds in recent five years. We wish our review would offer a new thinking in the design and optimization of the compounds in the research and development of the new drugs.

Contents
1 Introduction
2 Amide bioisosteric replacement in lead compounds optimization
2.1 Increasing the target potency and selectivity
2.2 Improving the drug-likeness of the lead compounds
2.3 Developing new structures to expand or break through the patents
2.4 Decreasing the difficulty of the synthesis of the compounds
3 Conclusion

Graphical abstract

关键词

酰胺 / 生物电子等排体 / 新药研发 / 先导化合物 / 结构优化

Key words

amide / bioisosteres / new drug research and development / lead compounds / optimization of structure

引用本文

引用格式 ▾

梅以成, 杨宝卫. 酰胺电子等排体在先导化合物优化中的应用[J]. 化学进展, 2016, 28(9): 1406-1416 DOI:10.7536/PC160414

Application of Amide Bioisosteres in the Optimization of Lead Compounds[J]. Progress in Chemistry, 2016, 28(9): 1406-1416 DOI:10.7536/PC160414

登录浏览全文

4963

注册一个新账户忘记密码

参考文献

原文顺序 | 出版日期 | 本文引用

[1] Langmuir I. J. Am. Chem. Soc., 1919, 41:1543.
[2] Friedman H L. Influence of Isosteric Replacements upon Biological Activity. Washington DC:NAS-NRS, 1951. 295.
[3] Thornber C W. Chem. Soc. Rev., 1979, 8:563.
[4] Burger A. Medicinal Chemistry. 3rd ed. NY:Wiley-Interscience, 1970. 127.
[5] Burger A. Prog. Drug Res., 1991, 37:287.
[6] Ghose A K, Viswanadhan V N, Wendoloski J J. J. Comb. Chem., 1999, 1:55.
[7] Brandts J F, Halvorson H R, Brennan M. Biochemistry, 1975, 14:4953.
[8] D rwald F Z. Lead Optimization for Medicinal Chemists:Pharmacokinetic Properties of Functional Groups and Organic Compounds. Weinheim:Wiley-VCH, 2012. 605.
[9] Meanwell N A. J. Med. Chem., 2011, 54:2529.
[10] Patani G A, LaVoie E J. Chem. Rev., 1996, 96:3147.
[11] Gauthier J Y, Chauret N, Cromlish W, Desmarais S, Duong L T, Falgueyret J P, Kimmel D B, Lamontagne S, Léger S, LeRiche T, Li C S, Massé F, McKay D J, Nicoll-Griffith D A, Oballa R M, Palmer J T, Percival M D, Riendeau D, Robichaud J, Rodan G A, Rodan S B, Seto C, Thérien M, Truong V L, Venuti M C, Wesolowski G, Young R N, Zamboni R, Black W C. Bioorg. Med. Chem. Lett., 2008, 18:923.
[12] Sun S, Zhang Z, Kodumuru V, Pokrovskaia N, Fonarev J, Jia Q, Leung P Y, Tran J, Ratkay L G, McLaren D G, Radomski C, Chowdhury S, Fu J, Hubbard B, Winther M D, Dales N A. Bioorg. Med. Chem. Lett., 2014, 24:520.
[13] Vossenaar E R, Zendman A J, van Venrooij W J, Pruijn G J. BioEssays, 2003, 25:1106.
[14] Bicker K L, Anguish L, Chumanevich A A, Cameron M D, Cui X, Witalison E, Subramanian V, Zhang X, Chumanevich A P, Hofseth L J, Coonrod S A, Thompson P R. ACS. Med. Chem. Lett., 2012, 3:1081.
[15] Chumanevich A A, Causey C P, Knuckley B A, Jones J E, Poudyal D, Chumanevich A P, Davis T, Matesic L E, Thompson P R, Hofseth L J. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2011, 300:G929.
[16] Subramanian V, Knight J S, Parelkar S, Anguish L, Coonrod S A, Kaplan M J, Thompson P R. J. Med. Chem., 2015, 58:1337.
[17] Pastore V, Sabatier L, Enrique A, Marder M, Bruno-Blanch L E. Bioorg. Med. Chem., 2013, 21:841.
[18] Yauch R L, Gould S E, Scales S J, Tang T, Tian H, Ahn C P, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M, Kotkow K, Marsters J C, Rubin L L, de Sauvage F J. Nature, 2008, 455:406.
[19] Yang B, Hird A W, Russell D J, Fauber B P, Dakin L A, Zheng X, Su Q, Godin R, Brassil P, Devereaux E, Janetka J W. Bioorg. Med. Chem. Lett., 2012, 22:4907.
[20] Staben S T, Siu M, Goldsmith R, Olivero A G, Do S, Burdick D J, Heffron T P, Dotson J, Sutherlin D P, Zhu B Y, Tsui V, Le H, Lee L, Lesnick J, Lewis C, Murray J M, Nonomiya J, Pang J, Prior W W, Salphati L, Rouge L, Sampath D, Sideris S, Wiesmann C, Wu P. Bioorg. Med. Chem. Lett., 2011, 21:4054.
[21] Staben S T, Blaquiere N, Tsui V, Kolesnikov A, Do S, Bradley E K, Dotson J, Goldsmith R, Heffron T P, Lesnick J, Lewis C, Murray J, Nonomiya J, Olivero A G, Pang J, Rouge L, Salphati L, Wei B, Wiesmann C, Wu P. Bioorg. Med. Chem. Lett., 2013, 23:897.
[22] 韩春燕(Han C Y), 李燕(Li Y), 刘刚(Liu G). 化学进展(Progress in Chemistry), 2008, 20(9):1335.
[23] Yang Z H, Li X, Ma H K, Zheng J Y, Zhen X C, Zhang X H. Bioorg. Med. Chem. Lett., 2014, 24:152.
[24] Brown M L, Aaron W, Austin R J, Chong A, Huang T, Jiang B, Kaizerman J A, Lee G, Lucas B S, McMinn D L, Orf J, Rong M, Toteva M M, Xu G, Ye Q, Zhong W, De Graffenreid M R, Wickramasinghe D, Powers J P, Hungate R, Johnson M G. Bioorg. Med. Chem. Lett., 2011, 21:5206.
[25] Isabel E, Mellon C, Boyd M J, Chauret N, Deschênes D, Desmarais S, Falgueyret J P, Gauthier J Y, Khougaz K, Lau C K, Léger S, Levorse D A, Li C S, Massé F, David Percival M, Roy B, Scheigetz J, Thérien M, Truong V L, Wesolowski G, Young R N, Zamboni R, Cameron Black W. Bioorg. Med. Chem. Lett., 2011, 21:920.
[26] Xia G, You X, Liu L, Liu H, Wang J, Shi Y, Li P, Xiong B, Liu X, Shen J. Eur. J. Med. Chem., 2013, 62:1.
[27] Nair A G, Wong M K C, Shu Y, Jiang Y, Jenh C H, Kim S H, Yang D Y, Zeng Q, Shao Y, Zawacki L G, Duo J, McGuinness B F, Carroll C D, Hobbs D W, Shih N Y, Rosenblum S B, Kozlowski J A. Bioorg. Med. Chem. Lett., 2014, 24:1085.
[28] Eastwood P, González J, Gómez E, Caturla F, Aguilar N, Mir M, Aiguadé J, Matassa V, Balagué C, Orellana A, Domínguez M. Bioorg. Med. Chem. Lett., 2011, 21:6253.
[29] Tan F, Morris P W, Skidgel R A, Erdos E G. J. Biol. Chem., 1993, 268:16631.
[30] Scarry S C, Rimoldi J M. Annu. Rep. Med. Chem., 2013, 48:91.
[31] Debenham J S, Graham T H, Verras A, Zhang Y, Clements M J, Kuethe J T, Madsen-Duggan C, Liu W, Bhatt U R, Chen D, Chen Q, Garcia-Calvo M, Geissler W M, He H, Li X, Lisnock J, Shen Z, Tong X, Tung E C,Wiltsie J, Xu S, Hale J J,Pinto S, Shen D M. Bioorg. Med. Chem. Lett., 2013, 23:6228.
[32] Graham T H, Shu M, Verras A, Chen Q, Garcia-Calvo M, Li X, Lisnock J, Tong X, Tung E C, Wiltsie J, Hale J J, Pinto S, Shen D M. Bioorg. Med. Chem. Lett., 2014, 24:1657.
[33] de la Fuente Revenga M, Fernandez-Saez N, Herrera-Arozamena C, Morales-Garcia J A, Alonso-Gil S, Perez-Castillo A, Caignard D H, Rivara S, Rodriguez-Franco M I. J. Med. Chem., 2015, 58:4998.
[34] Canales E, Carlson J S, Appleby T, Fenaux M, Lee J, Tian Y, Tirunagari N, Wong M, Watkins W J. Bioorg. Med. Chem. Lett., 2012, 22:4288.
[35] LaPlante S R, Bos M, Brochu C, Chabot C, Coulombe R, Gillard J R, Jakalian A, Poirier M, Rancourt J, Stammers T, Thavonekham B, Beaulieu P L, Kukolj G, Tsantrizos Y S. J. Med. Chem., 2014, 57:1845.
[36] Sun Z Y, Asberom T, Bara T, Bennett C, Burnett D, Chu I, Clader J, Cohen-Williams M, Cole D, Czarniecki M, Durkin J, Gallo G, Greenlee W, Josien H, Huang X, Hyde L, Jones N, Kzakevich I, Li H, Liu X, Lee J, Maccoss M, Mandal M B, McCracken T, Nomeir A, Mazzola R, Palani A, Parker E M, Pissarnitski D A, Qin J, Song L, Terracina G, Vicarel M, Voigt J, Xu R, Zhang L, Zhang Q, Zhao Z, Zhu X, Zhu Z. J. Med. Chem., 2012, 55:489.
[37] Hegen M, Gaestel M, Nickerson-Nutter C L, Lin L L, Telliez J B. J. Immunol., 2006, 177:1913.
[38] Xiao D, Zhu X,Sofolarides M, Degrado S, Shao N, Rao A, Chen X, Aslanian R, Fossetta J, Tian F, Trivedi P, Lundell D, Palani A. Bioorg. Med. Chem. Lett., 2014, 24:3609.
[39] Morandi F, Caselli E, Morandi S, Focia P J, Blazquez J, Shoichet B K, Prati F. J. Am. Chem. Soc., 2003, 125:685.
[40] Caselli E, Romagnoli C, Vahabi R, Taracila M A, Bonomo R A, Prati F. J. Med. Chem., 2015, 58:5445.