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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Azabicyclo Compounds/chemical synthesis , Methylurea Compounds/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrazoles/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Inhalation , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Azabicyclo Compounds/pharmacokinetics , Azabicyclo Compounds/pharmacology , Binding Sites , Cell Membrane Permeability , Crystallography, X-Ray , Dogs , Drug Stability , Humans , In Vitro Techniques , Kinetics , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Methylurea Compounds/pharmacokinetics , Methylurea Compounds/pharmacology , Models, Molecular , Protein Binding , Protein Conformation , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Solubility , Surface Plasmon Resonance , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
Xenobiotics, including drugs, can influence cytochrome P450 (CYP) activity by upregulating the transcription of CYP genes. To minimize potential drug interactions, it is important to ascertain whether a compound will be an inducer of CYP enzymes early in the development of new therapeutic agents. In vivo and in vitro studies are reported that demonstrate the use of liver and intestinal slices as an in vitro model to predict potential CYP induction in vivo. Rat liver slices and intestinal slices were incubated, for 24 h and 6 h, respectively, with beta-naphthoflavone (betaNF), phenobarbital (PB) or dexamethasone (DEX). In an in vivo study, rats were treated with the same compounds for 3 days. In vivo and in vitro CYP mRNA levels were measured by using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). In addition, CYP enzyme activities were determined in rat liver slices after 48 h incubation. In both rat liver and intestinal slices, betaNF significantly induced CYP1A1, CYP1A2 and CYP2B1 mRNA levels. PB significantly induced CYP2B1. In liver slices a minor induction of CYP1A1 and CYP3A1 by PB was observed, whereas DEX significantly induced CYP3A1, CYP2B1 and CYP1A2 mRNA levels. The induction profiles (qualitative and quantitative) observed in vivo and in vitro are quite similar. All together, these data demonstrate that liver and intestinal slices are a useful and predictive tool to study CYP induction.
