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Discovery of 8-Amino-imidazo[1,5- a ]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis

Journal Article · · ACS Medicinal Chemistry Letters
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  1. Merck Research Lab., Rahway, NJ (United States)
  2. WuXi PharmaTech Co. Ltd, Shanghai (China)
+ Show Author Affiliations
Bruton’s tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
USDOE
OSTI ID:
1404965
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 2 Vol. 7; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (11)

Ibrutinib: First Global Approval journal January 2014
Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia journal January 1993
Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis journal August 2014
Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection journal December 2010
Bruton’s Tyrosine Kinase Inhibitors: Approaches to Potent and Selective Inhibition, Preclinical and Clinical Evaluation for Inflammatory Diseases and B Cell Malignancies journal March 2012
The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases journal January 1993
Pfizer's JAK inhibitor sails through phase 3 in rheumatoid arthritis journal June 2011
Targeting Bruton's tyrosine kinase in B cell malignancies journal March 2014
Emerging cell and cytokine targets in rheumatoid arthritis journal November 2013
Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib journal June 2014
The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells journal January 2011

Cited By (4)

A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC–HRMS monitoring of the reaction pathway journal November 2017
Pharmacophore modeling and virtual screening in search of novel Bruton’s tyrosine kinase inhibitors journal June 2019
Investigation of rotameric conformations of substituted imidazo-[1,2- a ]pyrazine: experimental and theoretical approaches journal January 2018
Combined pharmacophore, virtual screening and molecular dynamics studies to identify Bruton’s tyrosine kinase inhibitors journal January 2018

Figures / Tables (12)

Figure 1(p. 2)figure Figure 1
Scheme 1(p. 2)figure Scheme 1
Scheme 2(p. 2)figure Scheme 2
Scheme 3(p. 2)figure Scheme 3
Table 1(p. 3)table Table 1
Table 2(p. 4)table Table 2
Table 3(p. 4)table Table 3
Table 4(p. 4)table Table 4
Table 5(p. 4)table Table 5
Figure 2(p. 5)figure Figure 2
Figure 3(p. 5)figure Figure 3
Table 6(p. 5)table Table 6

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Amides
Inhibitors
Peptides and proteins
Selectivity
Structure activity relationship