Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor

被引：184

作者：

Measom, Nicholas D. ^{[1
,2
]}

Down, Kenneth D. ^{[1
]}

Hirst, David J. ^{[1
]}

Jamieson, Craig ^{[2
]}

Manas, Eric S. ^{[3
]}

Patel, Vipulkumar K. ^{[1
]}

Somers, Don O. ^{[1
]}

机构：

[1] GlaxoSmithKline, Med Res Ctr, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[2] Univ Strathclyde, Dept Pure & Appl Chem, Thomas Graham Bldg,295 Cathedral St, Glasgow G1 1XL, Lanark, Scotland

[3] GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA 19426 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 01期

关键词：

LpPLA(2); bicyclo[1.1.1]pentane; bioisostere; darapladib; cardiovascular disease; physicochemical; ACTIVATING-FACTOR ACETYLHYDROLASE; LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE-A2; CARDIOVASCULAR OUTCOMES; BIOLOGICAL EVALUATION; MISSENSE MUTATION; A(2) INHIBITOR; RISK-FACTOR; DISEASE; INFLAMMATION; DEFICIENCY;

D O I：

10.1021/acsmedchemlett.6b00281

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA(2) inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

引用

页码：43 / 48

页数：6

共 50 条

[1]

Andrews MD, 2012, PCT Int Appl., Patent No. [2012137089, WO2012137089, 02012137089]

[2] POLAR SUBSTITUENT EFFECTS IN 1,3-DISUBSTITUTED BICYCLO[1.1.1]PENTANES [J].

APPLEQUIST, DE ;

RENKEN, TL ;

WHEELER, JW .

JOURNAL OF ORGANIC CHEMISTRY, 1982, 47 (25) :4985-4995

[3] CONCERNING THE SYNTHESIS OF [1.1.1]PROPELLANE [J].

BELZNER, J ;

BUNZ, U ;

SEMMLER, K ;

SZEIMIES, G ;

OPITZ, K ;

SCHLUTER, AD .

CHEMISCHE BERICHTE, 1989, 122 (02) :397-398

[4]

Bennett J.E.B.L., 2012, Substituted Diaminocarboxamide and Diaminocarbonitrile Pyrimidines, Compositions Thereof, and Methods of Treatment Therewith, Patent No. [WO2012145569A1, 2012145569]

[5] 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

[6] Association of lipoprotein-associated phospholipase A2 levels with coronary artery disease risk factors, angiographic coronary artery disease, and major adverse events at follow-up [J].

Brilakis, ES ;

McConnell, JP ;

Lennon, RJ ;

Elesber, AA ;

Meyer, JG ;

Berger, PB .

EUROPEAN HEART JOURNAL, 2005, 26 (02) :137-144

[7] Phospholipase A2 Biochemistry [J].

Burke, John E. ;

Dennis, Edward A. .

CARDIOVASCULAR DRUGS AND THERAPY, 2009, 23 (01) :49-59

[8] TRIS(TRIMETHYLSILYL)SILANE - A NEW REDUCING AGENT [J].

CHATGILIALOGLU, C ;

GRILLER, D ;

LESAGE, M .

JOURNAL OF ORGANIC CHEMISTRY, 1988, 53 (15) :3641-3642

[9] Iridium-Catalyzed Reduction of Secondary Amides to Secondary Amines and Imines by Diethylsilane [J].

Cheng, Chen ;

Brookhart, Maurice .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2012, 134 (28) :11304-11307

[10] Synthesis and biological evaluation of 2-(3′-(1H-tetrazol-5-yl) bicyclo[1.1.1]pent-1-yl)glycine (S-TBPG), a novel mGlu1 receptor antagonist [J].

Costantino, G ;

Maltoni, K ;

Marinozzi, M ;

Camaioni, E ;

Prezeau, L ;

Pin, JP ;

Pellicciari, R .

BIOORGANIC & MEDICINAL CHEMISTRY, 2001, 9 (02) :221-227

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