Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1

Kai Ding; Ziyuan Zhou; Shuo Zhou; Yaxia Yuan; Kyungbo Kim; Ting Zhang; Xirong Zheng; Fang Zheng; Chang Guo Zhan

doi:10.1016/j.bmcl.2018.02.011

Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1

Kai Ding
, Ziyuan Zhou
, Shuo Zhou
, Yaxia Yuan
, Kyungbo Kim
, Ting Zhang
, Xirong Zheng
, Fang Zheng
, Chang Guo Zhan

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE₂ without blocking the normal biosynthesis of other prostanoids including homeostatic PGE₂. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX isozymes.

Original language	English
Pages (from-to)	858-862
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	5
DOIs	https://doi.org/10.1016/j.bmcl.2018.02.011
State	Published - Mar 1 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Ltd

Funding

This work was supported in part by the funding of the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy, the National Science Foundation (NSF grant CHE-1111761), and the National Institutes of Health via the National Center for Advancing Translational Sciences (UL1TR001998) grant. The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on a Dell Supercomputer Cluster consisting of 388 nodes or 4,816 processors.

Funders	Funder number
National Institutes of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)	UL1TR001998
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China	1111761

Keywords

Anti-inflammatory drugs
Barbituric acid
Pyrazole
mPGES-1 inhibitor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2018.02.011

Cite this

Ding, K., Zhou, Z., Zhou, S., Yuan, Y., Kim, K., Zhang, T., Zheng, X., Zheng, F., & Zhan, C. G. (2018). Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1. Bioorganic and Medicinal Chemistry Letters, 28(5), 858-862. https://doi.org/10.1016/j.bmcl.2018.02.011

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title = "Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1",

abstract = "Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE2 without blocking the normal biosynthesis of other prostanoids including homeostatic PGE2. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX isozymes.",

keywords = "Anti-inflammatory drugs, Barbituric acid, Pyrazole, mPGES-1 inhibitor",

author = "Kai Ding and Ziyuan Zhou and Shuo Zhou and Yaxia Yuan and Kyungbo Kim and Ting Zhang and Xirong Zheng and Fang Zheng and Zhan, \{Chang Guo\}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2018",

month = mar,

day = "1",

doi = "10.1016/j.bmcl.2018.02.011",

language = "English",

volume = "28",

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Ding, K, Zhou, Z, Zhou, S, Yuan, Y, Kim, K, Zhang, T, Zheng, X, Zheng, F & Zhan, CG 2018, 'Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 5, pp. 858-862. https://doi.org/10.1016/j.bmcl.2018.02.011

Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1. / Ding, Kai; Zhou, Ziyuan; Zhou, Shuo et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 28, No. 5, 01.03.2018, p. 858-862.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1

AU - Ding, Kai

AU - Zhou, Ziyuan

AU - Zhou, Shuo

AU - Yuan, Yaxia

AU - Kim, Kyungbo

AU - Zhang, Ting

AU - Zheng, Xirong

AU - Zheng, Fang

AU - Zhan, Chang Guo

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE2 without blocking the normal biosynthesis of other prostanoids including homeostatic PGE2. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX isozymes.

AB - Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE2 without blocking the normal biosynthesis of other prostanoids including homeostatic PGE2. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX isozymes.

KW - Anti-inflammatory drugs

KW - Barbituric acid

KW - Pyrazole

KW - mPGES-1 inhibitor

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UR - https://www.scopus.com/pages/publications/85042027185#tab=citedBy

U2 - 10.1016/j.bmcl.2018.02.011

DO - 10.1016/j.bmcl.2018.02.011

M3 - Article

C2 - 29456107

AN - SCOPUS:85042027185

SN - 0960-894X

VL - 28

SP - 858

EP - 862

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 5

ER -

Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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