Discovery and evaluation of 1H-pyrrolo[2,3-b]pyridine based selective and reversible small molecule BTK inhibitors for the treatment of rheumatoid arthritis

被引：3

作者：

Thakkar, Mahesh ^{[1
]}

Bhuniya, Debnath ^{[1
]}

Kaduskar, Rahul ^{[1
]}

Mengawade, Tanaji ^{[1
]}

Naik, Keshav ^{[1
]}

Salunkhe, Videsh ^{[1
]}

Bhalerao, Amit ^{[1
]}

Kurhade, Santosh ^{[1
]}

Mavinahalli, Jagadeesh ^{[1
]}

Jain, Vaibhav ^{[1
]}

Petla, Rajkanth ^{[1
]}

Avaragolla, Satheesh ^{[1
]}

Ray, Swagatam ^{[1
]}

Rouduri, Sreekanth ^{[1
]}

Dhanave, Avinash ^{[1
]}

De, Siddhartha ^{[1
]}

Pathade, Vishal ^{[1
]}

Tambe, Ashwini ^{[1
]}

Raje, Amol A. ^{[1
]}

Madgula, Vamsi ^{[1
]}

Joshi, Sachin ^{[1
]}

Nadeem, Ahmed ^{[1
]}

Bala, Madhu ^{[1
]}

Umrani, Dhananjay ^{[1
]}

Hariharan, Narayanan ^{[1
]}

Kulkarni, Bheemashankar ^{[1
]}

Mookhtiar, Kasim A. ^{[1
]}

机构：

[1] Advinus Therapeut Ltd, Drug Discovery Unit, Plot 9,Phase 1,Rajiv Gandhi InfoTech Pk, Pune 411057, Maharashtra, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 08期

关键词：

BTK; Reversible; 1H-Pyrrolo[2,3-b]pyridine; Human whole blood; Kinase selectivity; Autoimmune diseases; Rheumatoid arthritis; BRUTONS TYROSINE KINASE; X-LINKED AGAMMAGLOBULINEMIA; COLLAGEN-INDUCED ARTHRITIS; B-CELL; POTENT; ACTIVATION; MECHANISM; SCAFFOLD; BEARING; FAMILY;

D O I：

10.1016/j.bmcl.2017.02.026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d] pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：1867 / 1873

页数：7

共 30 条

[1] Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space [J].

Alex, Alexander ;

Millan, David S. ;

Perez, Manuel ;

Wakenhut, Florian ;

Whitlock, Gavin A. .

MEDCHEMCOMM, 2011, 2 (07) :669-674

[2] Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I [J].

Arnold, LD ;

Calderwood, DJ ;

Dixon, RW ;

Johnston, DN ;

Kamens, JS ;

Munschauer, R ;

Rafferty, P ;

Ratnofsky, SE .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (19) :2167-2170

[3] Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia [J].

Byrd, John C. ;

Harrington, Bonnie ;

O'Brien, Susan ;

Jones, Jeffrey A. ;

Schuh, Anna ;

Devereux, Steve ;

Chaves, Jorge ;

Wierda, William G. ;

Awan, Farrukh T. ;

Brown, Jennifer R. ;

Hillmen, Peter ;

Stephens, Deborah M. ;

Ghia, Paolo ;

Barrientos, Jacqueline C. ;

Pagel, John M. ;

Woyach, Jennifer ;

Johnson, Dave ;

Huang, Jane ;

Wang, Xiaolin ;

Kaptein, Allard ;

Lannutti, Brian J. ;

Covey, Todd ;

Fardis, Maria ;

McGreivy, Jesse ;

Hamdy, Ahmed ;

Rothbaum, Wayne ;

Izumi, Raquel ;

Diacovo, Thomas G. ;

Johnson, Amy J. ;

Furman, Richard R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2016, 374 (04) :323-332

[4] Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis [J].

Di Paolo, Julie A. ;

Huang, Tao ;

Balazs, Mercedesz ;

Barbosa, James ;

Barck, Kai H. ;

Bravo, Brandon J. ;

Carano, Richard A. D. ;

Darrow, James ;

Davies, Douglas R. ;

DeForge, Laura E. ;

Diehl, Lauri ;

Ferrando, Ronald ;

Gallion, Steven L. ;

Giannetti, Anthony M. ;

Gribling, Peter ;

Hurez, Vincent ;

Hymowitz, Sarah G. ;

Jones, Randall ;

Kropf, Jeffrey E. ;

Lee, Wyne P. ;

Maciejewski, Patricia M. ;

Mitchell, Scott A. ;

Rong, Hong ;

Staker, Bart L. ;

Whitney, J. Andrew ;

Yeh, Sherry ;

Young, Wendy B. ;

Yu, Christine ;

Zhang, Juan ;

Reif, Karin ;

Currie, Kevin S. .

NATURE CHEMICAL BIOLOGY, 2011, 7 (01) :41-50

[5] Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans [J].

Evans, Erica K. ;

Tester, Richland ;

Aslanian, Sharon ;

Karp, Russell ;

Sheets, Michael ;

Labenski, Matthew T. ;

Witowski, Steven R. ;

Lounsbury, Heather ;

Chaturvedi, Prasoon ;

Mazdiyasni, Hormoz ;

Zhu, Zhendong ;

Nacht, Mariana ;

Freed, Martin I. ;

Petter, Russell C. ;

Dubrovskiy, Alex ;

Singh, Juswinder ;

Westlin, William F. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2013, 346 (02) :219-228

[6] The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy [J].

Honigberg, Lee A. ;

Smith, Ashley M. ;

Sirisawad, Mint ;

Verner, Erik ;

Loury, David ;

Chang, Betty ;

Li, Shyr ;

Pan, Zhengying ;

Thamm, Douglas H. ;

Miller, Richard A. ;

Buggy, Joseph J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (29) :13075-13080

[7] Modulation of collagen-induced arthritis by IL-4 and dexamethasone: the synergistic effect of IL-4 and dexamethasone on the resolution of CIA [J].

Kang, I ;

Lee, WW ;

Lee, YS .

IMMUNOPHARMACOLOGY, 2000, 49 (03) :317-324

[8] Intramolecular Hydrogen Bonding in Medicinal Chemistry [J].

Kuhn, Bernd ;

Mohr, Peter ;

Stahl, Martin .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (06) :2601-2611

[9] Significant Species Difference in Amide Hydrolysis of GDC-0834, a Novel Potent and Selective Bruton's Tyrosine Kinase Inhibitor [J].

Liu, Lichuan ;

Halladay, Jason S. ;

Shin, Young ;

Wong, Susan ;

Coraggio, Melis ;

La, Hank ;

Baumgardner, Matthew ;

Le, Hoa ;

Gopaul, Sashi ;

Boggs, Jason ;

Kuebler, Peter ;

Davis, John C., Jr. ;

Liao, X. Charlene ;

Lubach, Joseph W. ;

Deese, Alan ;

Sowell, C. Gregory ;

Currie, Kevin S. ;

Young, Wendy B. ;

Khojasteh, S. Cyrus ;

Hop, Cornelis E. C. A. ;

Wong, Harvey .

DRUG METABOLISM AND DISPOSITION, 2011, 39 (10) :1840-1849

[10] Antiarthritis Effect of a Novel Bruton's Tyrosine Kinase (BTK) Inhibitor in Rat Collagen-Induced Arthritis and Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling: Relationships between Inhibition of BTK Phosphorylation and Efficacy [J].

Liu, Lichuan ;

Di Paolo, Julie ;

Barbosa, Jim ;

Rong, Hong ;

Reif, Karin ;

Wong, Harvey .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2011, 338 (01) :154-163

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