Abstract
This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.
MeSH terms
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Administration, Inhalation
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Azabicyclo Compounds / chemical synthesis*
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Azabicyclo Compounds / pharmacokinetics
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Azabicyclo Compounds / pharmacology
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Binding Sites
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Cell Membrane Permeability
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Crystallography, X-Ray
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Dogs
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Drug Stability
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Humans
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In Vitro Techniques
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Kinetics
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Methylurea Compounds / chemical synthesis*
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Methylurea Compounds / pharmacokinetics
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Methylurea Compounds / pharmacology
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Models, Molecular
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Protein Binding
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Protein Conformation
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Pulmonary Disease, Chronic Obstructive / drug therapy*
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Rats
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Solubility
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Surface Plasmon Resonance
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Tumor Necrosis Factor-alpha / biosynthesis
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / chemistry
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Azabicyclo Compounds
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Methylurea Compounds
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Pyrazoles
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Tumor Necrosis Factor-alpha
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N-(1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylethyl)-1H-pyrazol-5-yl)-N'-((2-((3-(2-((2-hydroxyethyl)thio)phenyl)-1,2,4-triazolo(4,3-a)pyridin-6-yl)thio)phenyl)methyl)-urea
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p38 Mitogen-Activated Protein Kinases