Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation.

A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2)-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved.

Pulmonary delivery of a p38 α/β MAP kinase inhibitor: bioanalytical method validation and biodistribution in rat plasma and respiratory tissues.

PF-03715455, an inhaled p38 α/β mitogen-activated protein (MAP) kinase inhibitor (MAPK), has being identified as an agent with potential therapeutic action on lung diseases such as COPD and severe asthma. However, little is known about this MAPKs local and systemic pharmacokinetics after pulmonary delivery. Consequently, the aim of the present work was to develop and validate a method of extraction and quantification of PF-03715455 in rat plasma and lung tissues and to determine the drug biodistribution in plasma and respiratory tissues after intratracheal administration of the drug solution in rats.