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

被引：22

作者：

Deng, Xinxian ^{[1
,2
]}

Shen, Jian ^{[1
,3
]}

Zhu, Hui ^{[4
]}

Xiao, Jia ^{[1
]}

Sun, Ran ^{[1
]}

Xie, Fangzhou ^{[1
]}

Lam, Celine ^{[1
]}

Wang, Juntao ^{[1
]}

Qiao, Yixue ^{[1
]}

Tavallaie, Mojdeh S. ^{[1
]}

Hu, Yang ^{[1
]}

Due, Yi ^{[5
]}

Li, Jianqi ^{[2
]}

Fu, Lei ^{[1
]}

Jiang, Faqin ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Pharm, 800 Dongchuan Rd, Shanghai 200240, Peoples R China

[2] China State Inst Pharmaceut Ind, 285 Gebaini Rd, Shanghai 201203, Peoples R China

[3] Viva Biotech Ltd Shanghai, 334 Aidisheng Rd, Shanghai 201203, Peoples R China

[4] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Dept Endocrinol, Sch Med, 369 Zhizaoju Rd, Shanghai 200011, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2018年 / 26卷 / 04期

基金：

中国国家自然科学基金;

关键词：

DPP-4; inhibitor; Pyrazolo[1,5-alpha]pyrimidin-7(4H)-one derivatives; Structure-based drug design; Molecular docking; Anti-diabetic; DIPEPTIDYL-PEPTIDASE-IV; GLUCAGON-LIKE PEPTIDE-1; BIOLOGICAL EVALUATION; DISCOVERY; DERIVATIVES; OPTIMIZATION; ALOGLIPTIN; SCAFFOLD; ANALOGS;

D O I：

10.1016/j.bmc.2018.01.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：903 / 912

页数：10

共 50 条

[31] Lanthanide complexes containing 5-methyl-1,2,4-triazolo[1,5-a] pyrimidin-7(4H)-one and their therapeutic potential to fight leishmaniasis and Chagas disease
Caballero, Ana B.
Rodriguez-Dieguez, Antonio
Salas, Juan M.
Sanchez-Moreno, Manuel
Marin, Clotilde
Ramirez-Macias, Inmaculada
Santamaria-Diaz, Noelia
Gutierrez-Sanchez, Ramon
JOURNAL OF INORGANIC BIOCHEMISTRY, 2014, 138 : 39 - 46
[32] Ruthenium(III) complexes with monodentate 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one: Structural characterization, interaction with DNA and proteins
Fandzloch, Marzena
Wojtczak, Andrzej
Wisniewska, Joanna
Stefanczak, Krystian
Salas, Juan M.
Lakomska, Iwona
INORGANICA CHIMICA ACTA, 2016, 443 : 170 - 178
[33] Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors
Gao, Ying-Duo
Feng, Dennis
Sheridan, Robert P.
Scapin, Giovanna
Patel, Sangita B.
Wu, Joseph K.
Zhang, Xiaoping
Sinha-Roy, Ranabir
Thornberry, Nancy A.
Weber, Ann E.
Biftu, Tesfaye
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (14) : 3877 - 3879
[34] Water-Mediated Selective Synthesis of Pyrazolo[1,5-a]quinazolin-5(4H)-ones and [1,2,4]Triazolo[1,5-a]quinazolin-5(4H)-one via Copper-Catalyzed Cascade Reactions
Zhang, Xinying
Gao, Lin
Wang, Zhangxin
Fan, Xuesen
SYNTHETIC COMMUNICATIONS, 2015, 45 (21) : 2426 - 2435
[35] Identification of substituted pyrazolo[1,5-a]quinazolin-5(4H)-one as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors
Orvieto, Federica
Branca, Danila
Giomini, Claudia
Jones, Philip
Koch, Uwe
Ontoria, Jesus M.
Palumbi, Maria Cecilia
Rowley, Michael
Toniatti, Carlo
Muraglia, Ester
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (15) : 4196 - 4200
[36] In vitro and in vivo antiparasital activity against Trypanosoma cruzi of three novel 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one-based complexes
Caballero, Ana B.
Marin, Clotilde
Rodriguez-Dieguez, Antonio
Ramirez-Macias, Inmaculada
Barea, Elisa
Sanchez-Moreno, Manuel
Salas, Juan M.
JOURNAL OF INORGANIC BIOCHEMISTRY, 2011, 105 (06) : 770 - 776
[37] Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors
Le Roux, Jacques
Leriche, Caroline
Chamiot-Clerc, Philippe
Feutrill, John
Halley, Frank
Papin, David
Derimay, Nathalie
Mugler, Christelle
Grepin, Claudine
Schio, Laurent
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (02) : 454 - 459
[38] Hydrogen-bonded chains in 5-methyl-2-trifluoromethyl-1,2,4-triazolo[1,5-a]-pyrimidin-7(4H)-one and hydrogen-bonded chains of rings in 5-amino-3-trifluoromethyl-1H-1,2,4-triazole-5-methyl-2-trifluoromethyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (1/1), the co-crystal of a reaction product and one of its precursors
Boechat, N
Dutra, KDB
Valverde, AL
Wardell, SMSV
Low, JN
Glidewell, C
ACTA CRYSTALLOGRAPHICA SECTION C-STRUCTURAL CHEMISTRY, 2004, 60 : O733 - O736
[39] X-ray structure and multinuclear NMR studies of platinum(II) complexes with 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one
Lakomska, Iwona
Wojtczak, Andrzej
Sitkowski, Jerzy
Kozerski, Lech
Szlyk, Edward
POLYHEDRON, 2007, 26 (04) : 803 - 810
[40] Synthesis of 5-Methyl-1,2,4-triazolo[1,5-a]Pyrimidin-7(4H)-one - a Semi-Product of the Synthesis of Antiviral Drug Triazide® in the Conditions of Microwave Excitation
Baklykov, Artem, V
Rusinov, Gennady L.
Artem'ev, Grigory A.
Kopchuk, Dmitry S.
Zyryanov, Grigory, V
Rusinov, Vladimir L.
Charushin, Valery N.
PROCEEDINGS OF THE II INTERNATIONAL CONFERENCE: MODERN SYNTHETIC METHODOLOGIES FOR CREATING DRUGS AND FUNCTIONAL MATERIALS (MOSM2018), 2019, 2063

← 1 2 3 4 5 →