Discovery of novel bicyclic[3.3.0]proline peptidyl α-ketoamides as potent 3CL-protease inhibitors for SARS-CoV-2

被引：4

作者：

Chen, Xiaoxin ^{[1
,2
]}

Li, Peng ^{[3
]}

Huang, Jianzhou ^{[2
]}

Yang, Yaxun ^{[3
]}

Zhang, Haoyu ^{[3
]}

Wang, Zheng ^{[3
]}

Zhu, Zhenzhen ^{[3
]}

Wang, Jingjing ^{[3
]}

Zhang, Jianchen ^{[3
]}

Chen, Kevin ^{[3
]}

He, Haiying ^{[3
]}

Long, Chaofeng ^{[2
]}

Chen, Shuhui ^{[3
]}

机构：

[1] Sun Yat Sen Univ, Sch Pharmaceut Sci Shenzhen, Shenzhen 518107, Guangdong, Peoples R China

[2] Guangdong Raynovent Biotech Co Ltd, Guangzhou 200131, Guangdong, Peoples R China

[3] WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2023年 / 90卷

关键词：

SARS-CoV-2; 3-chymotrypsin-like cysteine protease; & alpha; -ketoamide; PROTEASE; OPTIMIZATION; P1;

D O I：

10.1016/j.bmcl.2023.129324

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The outbreak of SARS-CoV-2 has caused global crisis on health and economics. The multiple drug-drug interaction risk associated with ritonavir warrants specialized assessment before using Paxlovid. Here we report a multiple-round SAR study to provide a novel bicyclic[3.3.0]proline peptidyl a-ketoamide compound 4a, which is endowed with excellent antiviral activities and pharmacokinetic properties. Also, in vivo HCoV-OC43 neonatal mice model demonstrated compound 4a has good in vivo efficacy. Based on these properties, compound 4a worth further SAR optimization with the goal to develop compounds with better pharmacokinetic properties and finally to realize single agent efficacy in human.

引用

页数：6

共 21 条

[1] Estimating global, regional, and national daily and cumulative infections with SARS-CoV-2 through Nov 14, 2021: a statistical analysis [J].

Barber, Ryan M. ;

Sorensen, Reed J. D. ;

Pigott, David M. ;

Bisignano, Catherine ;

Carter, Austin ;

Amlag, Joanne O. ;

Collins, James K. ;

Abbafati, Cristiana ;

Adolph, Christopher ;

Allorant, Adrien ;

Aravkin, Aleksandr Y. ;

Bang-Jensen, Bree L. ;

Castro, Emma ;

Chakrabarti, Suman ;

Cogen, Rebecca M. ;

Combs, Emily ;

Comfort, Haley ;

Cooperrider, Kimberly ;

Dai, Xiaochen ;

Daoud, Farah ;

Deen, Amanda ;

Earl, Lucas ;

Erickson, Megan ;

Ewald, Samuel B. ;

Ferrari, Alize J. ;

Flaxman, Abraham D. ;

Frostad, Joseph Jon ;

Fullman, Nancy ;

Giles, John R. ;

Guo, Gaorui ;

He, Jiawei ;

Helak, Monika ;

Hulland, Erin N. ;

Huntley, Bethany M. ;

Lazzar-Atwood, Alice ;

LeGrand, Kate E. ;

Lim, Stephen S. ;

Lindstrom, Akiaja ;

Linebarger, Emily ;

Lozano, Rafael ;

Magistro, Beatrice ;

Malta, Deborah Carvalho ;

Mansson, Johan ;

Herrera, Ana M. Mantilla ;

Mokdad, Ali H. ;

Monasta, Lorenzo ;

Naghavi, Mohsen ;

Nomura, Shuhei ;

Odell, Christopher M. ;

Olana, Latera Tesfaye .

LANCET, 2022, 399 (10344) :2351-2380

[2] P1 and P1′ optimization of [3,4]-bicycloproline P2 incorporated tetrapeptidyl α-ketoamide based HCV protease inhibitors [J].

Chen, SH ;

Lamar, J ;

Yip, Y ;

Victor, F ;

Johnson, RB ;

Wang, QM ;

Glass, JI ;

Heinz, B ;

Colacino, J ;

Guo, DQ ;

Tebbe, M ;

Munroe, JE .

LETTERS IN DRUG DESIGN & DISCOVERY, 2005, 2 (02) :118-123

[3]

Chen X, 2023, Ketoamide derivative and application thereof, Patent No. [CN202111057236A, 202111057236]

[4]

Chen X, bioRxiv

[5]

Couzin-Frankel J, 2021, SCIENCE, V374, P799, DOI 10.1126/science.acx9605

[6] Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19 [J].

Hammond, Jennifer ;

Leister-Tebbe, Heidi ;

Gardner, Annie ;

Abreu, Paula ;

Bao, Weihang ;

Wisemandle, Wayne ;

Baniecki, MaryLynn ;

Hendrick, Victoria M. ;

Damle, Bharat ;

Simon-Campos, Abraham ;

Pypstra, Rienk ;

Rusnak, James M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2022, 386 (15) :1397-1408

[7] STEREOSPECIFIC SYNTHESIS OF PEPTIDYL ALPHA-KETO AMIDES AS INHIBITORS OF CALPAIN [J].

HARBESON, SL ;

ABELLEIRA, SM ;

AKIYAMA, A ;

BARRETT, R ;

CARROLL, RM ;

STRAUB, JA ;

TKACZ, JN ;

WU, CC ;

MUSSO, GF .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (18) :2918-2929

[8] EGCG, a green tea polyphenol, inhibits human coronavirus replication in vitro [J].

Jang, Minsu ;

Park, Rackhyun ;

Park, Yea-In ;

Cha, Yeo-Eun ;

Yamamoto, Ayane ;

Lee, Jin I. ;

Park, Junsoo .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2021, 547 :23-28

[9] Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors [J].

Jin, Zhenming ;

Du, Xiaoyu ;

Xu, Yechun ;

Deng, Yongqiang ;

Liu, Meiqin ;

Zhao, Yao ;

Zhang, Bing ;

Li, Xiaofeng ;

Zhang, Leike ;

Peng, Chao ;

Duan, Yinkai ;

Yu, Jing ;

Wang, Lin ;

Yang, Kailin ;

Liu, Fengjiang ;

Jiang, Rendi ;

Yang, Xinglou ;

You, Tian ;

Liu, Xiaoce ;

Yang, Xiuna ;

Bai, Fang ;

Liu, Hong ;

Liu, Xiang ;

Guddat, Luke W. ;

Xu, Wenqing ;

Xiao, Gengfu ;

Qin, Chengfeng ;

Shi, Zhengli ;

Jiang, Hualiang ;

Rao, Zihe ;

Yang, Haitao .

NATURE, 2020, 582 (7811) :289-+

[10] Novel P4 truncated tripeptidyl α-ketoamides as HCV protease inhibitors [J].

Lamar, J ;

Victor, F ;

Snyder, N ;

Johnson, RB ;

Wang, QM ;

Glass, JI ;

Chen, SH .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (01) :263-266

← 1 2 3 →