Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors

Xinxian Deng; Jian Shen; Hui Zhu; Jia Xiao; Ran Sun; Fangzhou Xie; Celine Lam; Juntao Wang; Yixue Qiao; Mojdeh S. Tavallaie; Yang Hu; Yi Du; Jianqi Li; Lei Fu; Faqin Jiang

doi:10.1016/j.bmc.2018.01.006

Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors

Xinxian Deng, Jian Shen, Hui Zhu, Jia Xiao, Ran Sun, Fangzhou Xie, Celine Lam, Juntao Wang, Yixue Qiao, Mojdeh S. Tavallaie, Yang Hu, Yi Du, Jianqi Li^*, Lei Fu, Faqin Jiang

^*Corresponding author for this work

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

22 Citations (Scopus)

Abstract

The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC₅₀: 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC₅₀: 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors.

Original language	English
Pages (from-to)	903-912
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	26
Issue number	4
DOIs	https://doi.org/10.1016/j.bmc.2018.01.006
Publication status	Published - 15 Feb 2018
Externally published	Yes

Keywords

Anti-diabetic
DPP-4 inhibitor
Molecular docking
Pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives
Structure-based drug design

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmc.2018.01.006

Cite this

Deng, X., Shen, J., Zhu, H., Xiao, J., Sun, R., Xie, F., Lam, C., Wang, J., Qiao, Y., Tavallaie, M. S., Hu, Y., Du, Y., Li, J., Fu, L., & Jiang, F. (2018). Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors. Bioorganic and Medicinal Chemistry, 26(4), 903-912. https://doi.org/10.1016/j.bmc.2018.01.006

@article{6614234b64db427f939f24927db9ed4c,

title = "Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors",

abstract = "The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC50: 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC50: 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors.",

keywords = "Anti-diabetic, DPP-4 inhibitor, Molecular docking, Pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives, Structure-based drug design",

author = "Xinxian Deng and Jian Shen and Hui Zhu and Jia Xiao and Ran Sun and Fangzhou Xie and Celine Lam and Juntao Wang and Yixue Qiao and Tavallaie, {Mojdeh S.} and Yang Hu and Yi Du and Jianqi Li and Lei Fu and Faqin Jiang",

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

year = "2018",

month = feb,

day = "15",

doi = "10.1016/j.bmc.2018.01.006",

language = "English",

volume = "26",

pages = "903--912",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

number = "4",

}

Deng, X, Shen, J, Zhu, H, Xiao, J, Sun, R, Xie, F, Lam, C, Wang, J, Qiao, Y, Tavallaie, MS, Hu, Y, Du, Y, Li, J, Fu, L & Jiang, F 2018, 'Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors', Bioorganic and Medicinal Chemistry, vol. 26, no. 4, pp. 903-912. https://doi.org/10.1016/j.bmc.2018.01.006

TY - JOUR

T1 - Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors

AU - Deng, Xinxian

AU - Shen, Jian

AU - Zhu, Hui

AU - Xiao, Jia

AU - Sun, Ran

AU - Xie, Fangzhou

AU - Lam, Celine

AU - Wang, Juntao

AU - Qiao, Yixue

AU - Tavallaie, Mojdeh S.

AU - Hu, Yang

AU - Du, Yi

AU - Li, Jianqi

AU - Fu, Lei

AU - Jiang, Faqin

PY - 2018/2/15

Y1 - 2018/2/15

N2 - The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC50: 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC50: 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors.

AB - The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC50: 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC50: 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors.

KW - Anti-diabetic

KW - DPP-4 inhibitor

KW - Molecular docking

KW - Pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives

KW - Structure-based drug design

UR - http://www.scopus.com/inward/record.url?scp=85040598193&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2018.01.006

DO - 10.1016/j.bmc.2018.01.006

M3 - Article

C2 - 29373269

AN - SCOPUS:85040598193

SN - 0968-0896

VL - 26

SP - 903

EP - 912

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 4

ER -

Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this