Preclinical Experimental and Mathematical Approaches for Assessing Effective Doses of Inhaled Drugs, Using Mometasone to Support Human Dose Predictions.

Background: Understanding the relationship between dose, lung exposure, and drug efficacy continues to be a challenging aspect of inhaled drug development. An experimental inhalation platform was developed using mometasone furoate to link rodent lung exposure to its in vivo pharmacodynamic (PD) effects.

Methods: We assessed the effect of mometasone delivered directly to the lung in two different rodent PD models of lung inflammation.

Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain.

Background: The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, in vitro and in vivo pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists.

Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.

1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids.