Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4

被引：11

作者：

Seganish, W. Michael ^{[1
]}

McElroy, William T. ^{[1
]}

Herr, R. Jason ^{[2
]}

Brumfield, Stephanie ^{[1
]}

Greenlee, William J. ^{[1
]}

Harding, James ^{[2
]}

Komanduri, Venukrishnan ^{[3
]}

Matasi, Julius ^{[1
]}

Prakash, Koraboina Chandra ^{[3
]}

Tulshian, Deen ^{[1
]}

Yang, Jinhai ^{[2
]}

Yet, Larry ^{[2
]}

Devito, Kristine ^{[4
]}

Fossetta, James ^{[5
]}

Garlisi, Charles G. ^{[4
]}

Lundell, Daniel ^{[5
]}

Niu, Xiaoda ^{[4
]}

Sondey, Christopher ^{[4
]}

机构：

[1] Merck Res Labs, Discovery Chem, Kenilworth, NJ 07033 USA

[2] AMRI, Dept Med Chem, Albany, NY 12203 USA

[3] AMRI Singapore Res Ctr, Dept Med Chem, Singapore 117525, Singapore

[4] Merck Res Labs, Vitro Pharmacol, Kenilworth, NJ 07033 USA

[5] Merck Res Labs, Resp & Immunol, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 16期

关键词：

IRAK4; Kinase; Inflammation; Structure activity relationships; Aminopyrimidine; INFLAMMATION; DISCOVERY; IRAK-4; IMMUNITY; INNATE;

D O I：

10.1016/j.bmcl.2015.05.097

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7 nM, an IC50 of 55 nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：3203 / 3207

页数：5

共 15 条

[1] Toll-like receptor signalling [J].

Akira, S ;

Takeda, K .

NATURE REVIEWS IMMUNOLOGY, 2004, 4 (07) :499-511

[2] Signalling mechanisms for Toll-like receptor-activated neutrophil exocytosis: key roles for interleukin-1-receptor-associated kinase-4 and phosphatidylinositol 3-kinase but not Toll/IL-1 receptor (TIR) domain-containing adaptor inducing IFN-β (TRIF) [J].

Brzezinska, Agnieszka A. ;

Johnson, Jennifer L. ;

Munafo, Daniela B. ;

Ellis, Beverly A. ;

Catz, Sergio D. .

IMMUNOLOGY, 2009, 127 (03) :386-397

[3] Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders [J].

Chaudhary, Divya ;

Robinson, Shaughnessy ;

Romero, Donna L. .

JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (01) :96-110

[4] Targeting innate immunity protein kinase signalling in inflammation [J].

Gaestel, Matthias ;

Kotlyarov, Alexey ;

Kracht, Michael .

NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (06) :480-499

[5] Ligand efficiency: a useful metric for lead selection [J].

Hopkins, AL ;

Groom, CR ;

Alex, A .

DRUG DISCOVERY TODAY, 2004, 9 (10) :430-431

[6] Advances in the Discovery of Small-Molecule IRAK4 Inhibitors [J].

Hynes, John, Jr. ;

Nair, Satheesh K. .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 49, 2014, 49 :117-133

[7] The Critical Role of Kinase Activity of Interleukin-1 Receptor-Associated Kinase 4 in Animal Models of Joint Inflammation [J].

Koziczak-Holbro, Magdalena ;

Littlewood-Evans, Amanda ;

Poellinger, Bernadette ;

Kovarik, Jiri ;

Dawson, Janet ;

Zenke, Gerhard ;

Burkhart, Christoph ;

Mueller, Matthias ;

Gram, Hermann .

ARTHRITIS AND RHEUMATISM, 2009, 60 (06) :1661-1671

[8] Cutting edge:: IL-1 receptor-associated kinase 4 structures reveal novel features and multiple conformations [J].

Kuglstatter, Andreas ;

Villasenor, Armando G. ;

Shaw, David ;

Lee, Simon W. ;

Tsing, Stan ;

Niu, Linghao ;

Song, Kyung W. ;

Barnett, Jim W. ;

Browner, Michelle F. .

JOURNAL OF IMMUNOLOGY, 2007, 178 (05) :2641-2645

[9] IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase [J].

Li, SY ;

Strelow, A ;

Fontana, EJ ;

Wesche, H .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (08) :5567-5572

[10] Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4 [J].

McElroy, William T. ;

Seganish, W. Michael ;

Herr, R. Jason ;

Harding, James ;

Yang, Jinhai ;

Yet, Larry ;

Komanduri, Venukrishnan ;

Prakash, Koraboina Chandra ;

Lavey, Brian ;

Tulshian, Deen ;

Greenlee, William J. ;

Sondey, Christopher ;

Fischmann, Thierry O. ;

Niu, Xiaoda .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (09) :1836-1841

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