Abstract
Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Discovery*
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Humans
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Imidazoles / chemistry
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Janus Kinase 1 / antagonists & inhibitors*
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Janus Kinase 1 / metabolism
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / metabolism
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Male
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Pyridines / administration & dosage
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Pyridines / chemistry
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Pyridines / pharmacology*
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Pyrroles / administration & dosage
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Imidazoles
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Protein Kinase Inhibitors
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Pyridines
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Pyrroles
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Janus Kinase 1
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Janus Kinase 2