Discovery of (S)-2-(1-(4-Amino-3-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-3-cyclopropyl-5-fluoroquinazolin-4(3H)-one (IHMT-PI3Kδ-372) as a Potent and Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease

Abstract

Accumulated pieces of evidence have shown that PI3Kδ plays a critical role in chronic obstructive pulmonary disease (COPD). Using a fragment-hybrid approach, we discovered a potent and selective PI3Kδ inhibitor ( S )-18. In the biochemical assay, ( S )-18 inhibits PI3Kδ (IC50 = 14 nM) with high selectivity over other class I PI3Ks (56∼83 fold). ( S )-18 also achieves good selectivity over other protein kinases in the kinome (S-score (35) = 0.015). In the cell, ( S )-18 selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308 but not other class I PI3K-mediated signaling. Additionally, ( S )-18 exhibits no apparent inhibitory effect on CYP isoforms except for a moderate effect on CYP2C9. Furthermore, it shows no apparent inhibitory activity against hERG (IC50 > 10 μM). In vivo, ( S )-18 displays favorable PK properties for inhaled delivery and improves lung function in a rodent model of pulmonary inflammation. These results suggest that ( S )-18 might be a new potential therapeutic candidate for COPD.

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions

“…The inhaled administration of 40 at 10 mg/kg showed clearance of 350 mL/min/kg and t 1/2 of 2.3 h in Sprague–Dawley rats. Compound 40 reduced pulmonary inflammation and increased lung function through inhaled delivery in the cigarette-smoke- and lipopolysaccharide-induced Sprague–Dawley rat model …”

“…Compound 40 reduced pulmonary inflammation and increased lung function through inhaled delivery in the cigarette-smoke-and lipopolysaccharideinduced Sprague−Dawley rat model. 132 Compound 41 (IC 50 values of 220, 200, 0.39, and 19 nM against PI3Kα, β, δ, and γ, respectively) and 42 (IC 50 values of 130, 160, 0.09, and 8.6 nM against PI3Kα, β, δ, and γ, respectively) were designed based on 1 using C-5-substituted quinazolinone as a bicyclic template and 1-cyclopropyl-Nmethylethan-1-amine as a short spacer. 133 The oral administration of compounds 41 and 42 resulted in TGI of 55% and 57% in the MOLT-4 xenograft mouse model at a dose of 10 mg/ kg.…”

4-Aminopyrazolopyrimidine scaffold and its deformation in the design of tyrosine and serine/threonine kinase inhibitors in medicinal chemistry

“…Further evaluation in cigarette-smokeand LPS-induced rodent model mimics showed that compound 63 could improve lung function and reduce the inflammatory pattern characteristics of COPD. 67 Additionally, patents WO2015069441 (ref. 68) and WO2016058084 (ref.…”

Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma

“… For instance, Idelalisib is a type of propeller-shaped inhibitor that is core-structured with quinazolin-4­(3 H )-one, and until now, there has been extensive medicinal chemistry exploration of chemotypes that give propeller-shaped structures for differential therapies. − Despite these advances, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy remains continuous interesting and important. During the course of our efforts in drug discovery and HCC therapy, − we started our exploration for PI3Kδ inhibitors by looking for a novel propeller-shaped chemotype via a scaffold-hopping strategy to replace quinazolin-4­(3 H )-one of Idelalisib. − Hence, we identified indazole as a new and suitable core to be potent, propeller-shaped, and selective PI3Kδ inhibitor . A total of 26 novel indazoles were designed and prepared to identify compound 9x , which exhibits good isoform selectivity, pharmaceutical profile, and a notably superior efficacy toward HCC compared to Idelalisib and Sorafenib.…”