Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors

被引：16
作者：
Bhide, Rajeev S. [1 ]
Keon, Alec [1 ]
Weigelt, Carolyn [2 ]
Sack, John S. [2 ]
Schmidt, Robert J. [1 ]
Lin, Shuqun [1 ]
Xiao, Hai-Yun [1 ]
Spergel, Steven H. [1 ]
Kempson, James [1 ]
Pitts, William J. [1 ]
Carman, Julie [3 ]
Poss, Michael A. [1 ]
机构：
[1] Bristol Myers Squibb Co, Discovery Chem, Res & Dev, Route 206 & Prov Line Rd, Princeton, NJ 08543 USA
[2] Bristol Myers Squibb Co, Mol Struct & Design, Res & Dev, Route 206 & Prov Line Rd, Princeton, NJ 08543 USA
[3] Bristol Myers Squibb Co, Immunosci Biol, Res & Dev, Route 206 & Prov Line Rd, Princeton, NJ 08543 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 21期
关键词：
IRAK4; 4,6-Diaminonicotinamide; Rheumatoid arthritis; Autoimmune disease; KINASE; 4; IRAK4; IMMUNITY; DISEASES; INNATE;
D O I：
10.1016/j.bmcl.2017.09.029
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay. (C) 2017 Elsevier Ltd. All rights reserved.
引用
收藏
页码：4908 / 4913
页数：6
相关论文
共 12 条
  • [1] Bhide RS, 2015, US, Patent No. [0274696 A1, 0274696A1]
  • [2] 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
    Chaudhary, Divya
    Robinson, Shaughnessy
    Romero, Donna L.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (01) : 96 - 110
  • [3] The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors
    Kawai, Taro
    Akira, Shizuo
    [J]. NATURE IMMUNOLOGY, 2010, 11 (05) : 373 - 384
  • [4] The Critical Role of Kinase Activity of Interleukin-1 Receptor-Associated Kinase 4 in Animal Models of Joint Inflammation
    Koziczak-Holbro, Magdalena
    Littlewood-Evans, Amanda
    Poellinger, Bernadette
    Kovarik, Jiri
    Dawson, Janet
    Zenke, Gerhard
    Burkhart, Christoph
    Mueller, Matthias
    Gram, Hermann
    [J]. ARTHRITIS AND RHEUMATISM, 2009, 60 (06): : 1661 - 1671
  • [5] Selective predisposition to bacterial infections in IRAK-4-deficient children:: IRAK-4-dependent TLRs are otherwise redundant in protective immunity
    Ku, Cheng-Lung
    von Bernuth, Horst
    Picard, Capucine
    Zhang, Shen-Ying
    Chang, Huey-Hsuan
    Yang, Kun
    Chrabieh, Maya
    Issekutz, Andrew C.
    Cunningham, Coleen K.
    Gallin, John
    Holland, Steven M.
    Roifman, Chaim
    Ehl, Stephan
    Smart, Joanne
    Tang, Mimi
    Barrat, Franck J.
    Levy, Ofer
    McDonald, Douglas
    Day-Good, Noorbibi K.
    Miller, Richard
    Takada, Hidetoshi
    Hara, Toshiro
    Al-Hajjar, Sami
    Al-Ghonaium, Abdulaziz
    Speert, David
    Sanlaville, Damien
    Li, Xiaoxia
    Geissmann, Frederic
    Vivier, Eric
    Marodi, Laszlo
    Garty, Ben-Zion
    Chapel, Helen
    Rodriguez-Gallego, Carlos
    Bossuyt, Xavier
    Abel, Laurent
    Puel, Anne
    Casanova, Jean-Laurent
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (10) : 2407 - 2422
  • [6] Cutting edge:: IL-1 receptor-associated kinase 4 structures reveal novel features and multiple conformations
    Kuglstatter, Andreas
    Villasenor, Armando G.
    Shaw, David
    Lee, Simon W.
    Tsing, Stan
    Niu, Linghao
    Song, Kyung W.
    Barnett, Jim W.
    Browner, Michelle F.
    [J]. JOURNAL OF IMMUNOLOGY, 2007, 178 (05) : 2641 - 2645
  • [7] Lee K, 2016, MEDI 261 ABSTR PAP 2
  • [8] Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment -Based Drug Design
    Lee, Katherine L.
    Ambler, Catherine M.
    Anderson, David R.
    Boscoe, Brian P.
    Bree, Andrea G.
    Brodfuehrer, Joanne I.
    Chang, Jeanne S.
    Choi, Chulho
    Chung, Seungwon
    Curran, Kevin J.
    Day, Jacqueline E.
    Dehnhardt, Christoph M.
    Dower, Ken
    Drozda, Susan E.
    Frisbie, Richard K.
    Gavrin, Lori K.
    Goldberg, Joel A.
    Han, Seungil
    Hegen, Martin
    Hepworth, David
    Hope, Heidi R.
    Kamtekar, Satwik
    Kilty, Iain C.
    Lee, Arthur
    Ling, Lih-Ling
    Lovering, Frank E.
    Lowe, Michael D.
    Mathias, John P.
    Morgan, Heidi M.
    Murphy, Elizabeth A.
    Papaioannou, Nikolaos
    Patny, Akshay
    Pierce, Betsy S.
    Rao, Vikram R.
    Saiah, Eddine
    Samardjiev, Ivan J.
    Samas, Brian M.
    Shen, Marina W. H.
    Shin, Julia H.
    Soutter, Holly H.
    Strohbach, Joseph W.
    Symanowicz, Peter T.
    Thomason, Jennifer R.
    Trzupek, John D.
    Vargas, Richard
    Vincent, Fabien
    Yan, Jiangli
    Zapf, Christoph W.
    Wright, Stephen W.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (13) : 5521 - 5542
  • [9] Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity
    Navegantes, Kely Campos
    Gomes, Rafaelli de Souza
    Tartari Pereira, Priscilla Aparecida
    Czaikoski, Paula Giselle
    Mares Azevedo, Carolina Heitmann
    Monteiro, Marta Chagas
    [J]. JOURNAL OF TRANSLATIONAL MEDICINE, 2017, 15
  • [10] Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
    Picard, Capucine
    Casanova, Jean-Laurent
    Puel, Anne
    [J]. CLINICAL MICROBIOLOGY REVIEWS, 2011, 24 (03) : 490 - 497
12