Use of Osmotic Pumps to Establish the Pharmacokinetic-Pharmacodynamic Relationship and Define Desirable Human Performance Characteristics for Aggrecan...
Basic Information
ID: ALA4425099
Journal: J Med Chem
Title: Use of Osmotic Pumps to Establish the Pharmacokinetic-Pharmacodynamic Relationship and Define Desirable Human Performance Characteristics for Aggrecanase Inhibitors.
Authors: Wiley MR, Durham TB, Adams LA, Chambers MG, Lin C, Liu C, Marimuthu J, Mitchell PG, Mudra DR, Swearingen CA, Toth JL, Weller JM, Thirunavukkarasu K.
Abstract: The development of reliable relationships between in vivo target engagement, pharmacodynamic activity, and efficacy in chronic disease models is beneficial for enabling hypothesis-driven drug discovery and facilitating the development of patient-focused candidate selection criteria. Toward those ends, osmotic infusion pumps can be useful for overcoming limitations in the PK properties of proof-of-concept (POC) compounds to accelerate the development of such relationships. In this report, we describe the application of this strategy to the development of hydantoin-derived aggrecanase inhibitors (eg, 3) for the treatment of osteoarthiritis (OA). Potent, selective inhibitors were efficacious in both chemical and surgical models of OA when exposures were sustained in excess of 10 times the plasma IC50. The use of these data for establishing patient-focused candidate selection criteria is exemplified with the characterization of compound 8, which is projected to sustain the desired level of target engagement at a dose of 45 mg qd.
CiteXplore: 27194201
DOI: 10.1021/acs.jmedchem.6b00398
Patent ID: ┄