Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases

Oral PI3Kδ inhibitors such
as Idelalisib and Duvelisib have
shown efficacy as anticancer agents and Idelalisib has been approved
for the treatment of three B-cell cancers. However, Idelalisib has
a black box warning on its product label regarding the risks of fatal
and serious toxicities including hepatic toxicity, severe diarrhea,
colitis, pneumonitis, infections, and intestinal perforation. Some
of these side effects are mechanism-related and could hinder the development
of Idelalisib for less severe conditions. For respiratory diseases,
compounds administered by inhalation are delivered directly to the
site of action and may improve the therapeutic index of a drug, minimizing
undesired side effects. This work describes the discovery and optimization
of inhaled PI3Kδ inhibitors intended for the treatment of severe
asthma and COPD. Once the potency was in the desired range, efforts
were focused on identifying the particular physicochemical properties
that could translate into better lung retention. This medicinal chemistry
exercise led to the identification of LAS195319 as a candidate for
clinical development.