Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors

被引：40

作者：

Chen, Xinde ^{[1
]}

Xu, Wenwei ^{[1
]}

Wang, Kai ^{[1
]}

Mo, Mingguang ^{[1
]}

Zhang, Wei ^{[1
]}

Du, Lili ^{[1
]}

Yuan, Xiaojing ^{[1
]}

Xu, Yechun ^{[1
]}

Wang, Yiping ^{[1
]}

Shen, Jianhua ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 21期

关键词：

PLATELET-ACTIVATING-FACTOR; ZINC-DEPENDENT INHIBITORS; LOW-DENSITY-LIPOPROTEIN; FACTOR ACETYLHYDROLASE; ACTIVE INHIBITORS; BIOLOGICAL EVALUATION; TRIAZOLE DERIVATIVES; DARAPLADIB; LP-PLA(2); DESIGN;

D O I：

10.1021/acs.jmedchem.5b01024

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA(2) inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.

引用

页码：8529 / 8541

页数：13

共 58 条

[1] Diabetes and Hypercholesterolemia Increase Blood-Brain Barrier Permeability and Brain Amyloid Deposition: Beneficial Effects of the LpPLA2 Inhibitor Darapladib [J].

Acharya, Nimish K. ;

Levin, Eli C. ;

Clifford, Peter M. ;

Han, Min ;

Tourtellotte, Ryan ;

Chamberlain, Dean ;

Pollaro, Michael ;

Coretti, Nicholas J. ;

Kosciuk, Mary C. ;

Nagele, Eric P. ;

DeMarshall, Cassandra ;

Freeman, Theresa ;

Shi, Yi ;

Guan, Chenbing ;

Macphee, Colin H. ;

Wilensky, Robert L. ;

Nagele, Robert G. .

JOURNAL OF ALZHEIMERS DISEASE, 2013, 35 (01) :179-198

[2] Post Groebke-Blackburn multicomponent protocol: Synthesis of new polyfunctional imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives as potential antimicrobial agents [J].

Al-Tel, Taleb H. ;

Al-Qawasmeh, Raed A. .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2010, 45 (12) :5848-5855

[3] Cellular source(s) of platelet-activating-factor acetylhydrolase activity in plasma [J].

Asano, K ;

Okamoto, S ;

Fukunaga, K ;

Shiomi, T ;

Mori, T ;

Iwata, M ;

Ikeda, Y ;

Yamaguchi, K .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 261 (02) :511-514

[4] Platelet-activating factor acetylhydrolase is mainly associated with electronegative low-density lipoprotein subfraction [J].

Benítez, S ;

Sánchez-Quesada, JL ;

Ribas, V ;

Jorba, O ;

Blanco-Vaca, F ;

González-Sastre, F ;

Ordóñez-Llanos, J .

CIRCULATION, 2003, 108 (01) :92-96

[5] Design and Synthesis of a Novel Series of Bicyclic Heterocycles As Potent γ-Secretase Modulators [J].

Bischoff, Francois ;

Berthelot, Didier ;

De Cleyn, Michel ;

Macdonald, Gregor ;

Minne, Garrett ;

Oehlrich, Daniel ;

Pieters, Serge ;

Surkyn, Michel ;

Trabanco, Andres A. ;

Tresadern, Gary ;

Van Brandt, Sven ;

Velter, Ingrid ;

Zaja, Mirko ;

Borghys, Herman ;

Masungi, Chantal ;

Mercken, Marc ;

Gijsen, Harrie J. M. .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (21) :9089-9106

[6] The identification of clinical candidate SB-480848:: A potent inhibitor of lipoprotein-associated phospholipase A2 [J].

Blackie, JA ;

Bloomer, JC ;

Brown, MJB ;

Cheng, HY ;

Hammond, B ;

Hickey, DMB ;

Ife, RJ ;

Leach, CA ;

Lewis, VA ;

Macphee, CH ;

Milliner, KJ ;

Moores, KE ;

Pinto, IL ;

Smith, SA ;

Stansfield, IG ;

Stanway, SJ ;

Taylor, MA ;

Theobald, CJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (06) :1067-1070

[7] The discoverv of SB-435495:: A potent, orally active inhibitor of lipoprotein-associated phospholipase A2 for evaluation in man [J].

Blackie, JA ;

Bloomer, JC ;

Brown, MJB ;

Cheng, HY ;

Elliott, RL ;

Hammond, B ;

Hickey, DMB ;

Ife, RJ ;

Leach, CA ;

Lewis, VA ;

Macphee, CH ;

Milliner, KJ ;

Moores, KE ;

Pinto, IL ;

Smith, SA ;

Stansfield, IG ;

Stanway, SJ ;

Taylor, MA ;

Theobald, CJ ;

Whittaker, CM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (18) :2603-2606

[8] 1-(Arylpiperazinylamidoalkyl)-pyrimidones:: Orally active inhibitors of lipoprotein-associated phospholipase A2 [J].

Bloomer, JC ;

Boyd, HF ;

Hickey, DMB ;

Ife, RJ ;

Leach, CA ;

Macphee, CH ;

Milliner, KJ ;

Pinto, IL ;

Rawlings, DA ;

Smith, SA ;

Stansfield, IG ;

Stanway, SJ ;

Taylor, MA ;

Theobald, CJ ;

Whittaker, CM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (14) :1925-1929

[9] 2-(Alkylthio)pyrimidin-4-ones as novel, reversible inhibitors of lipoprotein-associated phospholipase A2 [J].

Boyd, HF ;

Flynn, ST ;

Hickey, DMB ;

Ife, RJ ;

Jones, M ;

Leach, CA ;

Macphee, CH ;

Milliner, KJ ;

Rawlings, DA ;

Slingsby, BP ;

Smith, SA ;

Stansfield, IG ;

Tew, DG ;

Theobald, CJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (04) :395-398

[10] Potent, orally active inhibitors of lipoprotein-associated phospholipase A2:: 1-(biphenylmethylamidoalkyl)-pyrimidones [J].

Boyd, HF ;

Fell, SCM ;

Hickey, DMB ;

Ife, RJ ;

Leach, CA ;

Macphee, CH ;

Milliner, KJ ;

Pinto, IL ;

Rawlings, DA ;

Smith, SA ;

Stansfield, IG ;

Stanway, SJ ;

Theobald, CJ ;

Whittaker, CM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (01) :51-55

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