Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor

被引：30

作者：

Zheng, Barbara ^{[1
]}

D'Andrea, Stanley V. ^{[1
]}

Sun, Li-Qiang ^{[1
]}

Wang, Alan Xiangdong ^{[1
]}

Chen, Yan ^{[1
]}

Hrnciar, Peter ^{[1
]}

Friborg, Jacques ^{[1
]}

Falk, Paul ^{[1
]}

Hernandez, Dennis ^{[1
]}

Yu, Fei ^{[1
]}

Sheaffer, Amy K. ^{[1
]}

Knipe, Jay O. ^{[1
]}

Mosure, Kathy ^{[1
]}

Rajamani, Ramkumar ^{[1
]}

Good, Andrew C. ^{[1
]}

Kish, Kevin ^{[2
]}

Tredup, Jeffrey ^{[2
]}

Klei, Herbert E. ^{[2
]}

Paruchuri, Manjula ^{[3
]}

Ng, Alicia ^{[1
]}

Gao, Qi ^{[1
]}

Rampulla, Richard A. ^{[4
]}

Mathur, Arvind ^{[4
]}

Meanwell, Nicholas A. ^{[1
]}

McPhee, Fiona ^{[1
]}

Scola, Paul M. ^{[1
]}

机构：

[1] Bristol Myers Squibb, Res & Dev, 5 Res Pkwy, Wallingford, CT 06492 USA

[2] Bristol Myers Squibb, Res & Dev, POB 5400, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb, Biol Proc Dev, 311 Pennington Rocky Hill Rd, Pennington, NJ 08534 USA

[4] Bristol Myers Squibb, Discovery Synth, Res & Dev, Route 206 & Prov Line Rd, Princeton, NJ 08543 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 02期

关键词：

Hepatitis C virus; NS3; protease; enzyme and replicon inhibitor; difluoromethylcyclopropyl amino acid; difluoromethyl; tripeptide acylsulfonamide; hydrogen-bond donor; GENOTYPE; 1; ASUNAPREVIR; INFECTION; DISCOVERY; ESTER;

D O I：

10.1021/acsmedchemlett.7b00503

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid.

引用

页码：143 / 148

页数：6

共 22 条

[1] HYDROGEN-BOND DONOR PROPERTIES OF THE DIFLUOROMETHYL GROUP
ERICKSON, JA
MCLOUGHLIN, JI
[J]. JOURNAL OF ORGANIC CHEMISTRY, 1995, 60 (06) : 1626 - 1631
[2] An efficient chiral synthesis of fluoro-containing amino acids:: N-benzyloxycarbonyl-2-amino-4,4-difluorobutyric acid methyl ester and its analogs
Hu, Zilun
Han, Wei
[J]. TETRAHEDRON LETTERS, 2008, 49 (05) : 901 - 902
[3] Hepatitis C virus NS3/4A protease
Kwong, AD
Kim, JL
Rao, G
Lipovsek, D
Raybuck, SA
[J]. ANTIVIRAL RESEARCH, 1998, 40 (1-2) : 1 - 18
[4] Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3SAR
Lamar, J
Hu, JD
Bueno, AB
Yang, HC
Guo, DQ
Copp, JD
McGee, J
Gitter, B
Timm, D
May, P
McCarthy, J
Chen, SH
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (01) : 239 - 243
[5] Current therapy for chronic hepatitis C: The role of direct-acting antivirals
Li, Guangdi
De Clercq, Erik
[J]. ANTIVIRAL RESEARCH, 2017, 142 : 83 - 122
[6] Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1
Lok, Anna S.
Gardiner, David F.
Lawitz, Eric
Martorell, Claudia
Everson, Gregory T.
Ghalib, Reem
Reindollar, Robert
Rustgi, Vinod
McPhee, Fiona
Wind-Rotolo, Megan
Persson, Anna
Zhu, Kurt
Dimitrova, Dessislava I.
Eley, Timothy
Guo, Tong
Grasela, Dennis M.
Pasquinelli, Claudio
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (03) : 216 - 224
[7] Hydrogen bonding in 1-carboxy-propanaminium nitrate
Messai, Amel
Benali-Cherif, Rim
Jeanneau, Erwann
Benali-Cherif, Nourredine
[J]. ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2012, 68 : O1307 - +
[8] α-ketoacids are potent slow binding inhibitors of the hepatitis C virus NS3 protease
Narjes, F
Brunetti, M
Colarusso, S
Gerlach, B
Koch, U
Biasiol, G
Fattori, D
De Francesco, R
Matassa, VG
Steinkühler, C
[J]. BIOCHEMISTRY, 2000, 39 (07) : 1849 - 1861
[9] A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCVNS3 protease
Narjes, F
Koehler, KF
Koch, U
Gerlach, B
Colarusso, S
Steinkuhler, C
Brunetti, M
Altamura, S
De Francesco, R
Matassa, VG
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (04) : 701 - 704
[10] Daclatasvir plus Asunaprevir: First Global Approval
Poole, Raewyn M.
[J]. DRUGS, 2014, 74 (13) : 1559 - 1571

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