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Title: Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization

Journal Article · · ACS Medicinal Chemistry Letters
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Merck and Co., Inc., Boston, MA (United States)
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Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
USDOE
OSTI ID:
1404960
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 12 Vol. 7; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (16)

A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides journal January 1979
Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor journal August 2011
Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor journal September 2007
Getting Syk: spleen tyrosine kinase as a therapeutic target journal August 2014
Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell Specific Spleen Tyrosine Kinase Inhibitors journal February 2014
Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase journal April 2014
Overcoming Mutagenicity and Ion Channel Activity: Optimization of Selective Spleen Tyrosine Kinase Inhibitors journal February 2015
Discovery and Profiling of a Selective and Efficacious Syk Inhibitor journal February 2015
Structural Insights for Design of Potent Spleen Tyrosine Kinase Inhibitors from Crystallographic Analysis of Three Inhibitor Complexes journal April 2009
Specific Inhibition of Spleen Tyrosine Kinase Suppresses Leukocyte Immune Function and Inflammation in Animal Models of Rheumatoid Arthritis journal October 2011
Inhibition of Spleen Tyrosine Kinase Attenuates Allergen-Mediated Airway Constriction journal December 2013
Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia journal April 2010
The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling journal December 2010
Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy journal January 2013
Spleen tyrosine kinase (Syk) as a novel target for allergic asthma and rhinitis journal September 2005
Effects of Fostamatinib (R788), an Oral Spleen Tyrosine Kinase Inhibitor, on Health-related Quality of Life in Patients with Active Rheumatoid Arthritis: Analyses of Patient-reported Outcomes from a Randomized, Double-blind, Placebo-controlled Trial journal February 2013

Cited By (3)

Indolylboronic Acids: Preparation and Applications journal September 2019
Indolylboronic Acids: Preparation and Applications journal September 2019
BindingDB Entry 50048032: Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization. dataset January 2018

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Conformation
Indoles
Inhibitors
Peptides and proteins
Rodent models
Spleen tyrosine kinase
intramolecular hydrogen bond
structure-based drug design