Abstract
Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model.
Keywords:
Autoimmune diseases; IL-2; Immunomodulator; Janus kinase inhibitor; Organ transplant rejection.
Copyright © 2017 Elsevier Ltd. All rights reserved.
MeSH terms
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Adjuvants, Immunologic / administration & dosage
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Adjuvants, Immunologic / chemistry
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Adjuvants, Immunologic / pharmacology*
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Administration, Oral
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Animals
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Biological Availability
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Cell Membrane Permeability / drug effects
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Discovery*
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Female
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Graft Survival / drug effects
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Heart Transplantation
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Humans
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Janus Kinases / antagonists & inhibitors*
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Janus Kinases / metabolism
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Male
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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, Inbred ACI
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Rats, Inbred Lew
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Adjuvants, Immunologic
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Protein Kinase Inhibitors
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Pyridines
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Pyrroles
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Janus Kinases