Abstract
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
MeSH terms
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Administration, Oral
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Animals
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Antirheumatic Agents / chemical synthesis*
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Antirheumatic Agents / chemistry
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Antirheumatic Agents / pharmacology
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Arthritis, Experimental / drug therapy
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Arthritis, Experimental / etiology
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Biological Availability
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Cell Membrane Permeability
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Collagen
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Crystallography, X-Ray
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Dogs
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Haplorhini
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry
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Janus Kinase 1 / antagonists & inhibitors*
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Janus Kinase 1 / chemistry
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / chemistry
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Madin Darby Canine Kidney Cells
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Rats
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Stereoisomerism
Substances
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4-(2-(1-hydroxyethyl)imidazo(4,5-d)pyrrolo(2,3-b)pyridin-1(6H)-yl)cyclohexanecarbonitrile
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Antirheumatic Agents
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Heterocyclic Compounds, 3-Ring
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Imidazoles
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Isoenzymes
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Pyridines
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Pyrroles
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Collagen
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Janus Kinase 1
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Janus Kinase 2
Associated data
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PDB/4EHZ
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PDB/4F09
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PDB/4IVA
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PDB/4IVB
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PDB/4IVC
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PDB/4IVD