Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors

Abstract

Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction−reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.

Design of A Metabolically Stable Tritium‐Tracer of the PI3Kδ‐Inhibitor CDZ173 (Leniolisib) as a Tool to Study Liver Metabolites

“…AGC target settings were 5 9 10 5 and 1 9 10 4 for full MS and MS/MS, respectively. The polysiloxane background ion [C 2 H 6 SiO] 6 with m/z 445.12003 was used as lock mass.…”

“…To summarize, starting from the lead compound BEZ522 sophisticated SAR studies yielded the 3 rd generation PI3K δ inhibitor CDZ173 with improved biophysical properties, promising PK/PD and encouraging clinical results. As part of the preclinical program, the ADME properties of this compound were investigated in animal models.…”

Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland

“…By rearranging fragments of known oncologic drugs, his team improved the selectivity and potency of the compound toward other PI3Ks. After co‐crystallization of this hit with the protein, they ran a SAR study to improve the safety profile and activity of the new lead …”

“…After co-crystallization of this hit with the protein, they ran aS AR www.chemmedchem.org study to improvet he safety profile and activity of the new lead. [19,20] The Immunooncologya nd Immunomodulation session comprised three talks on Monday.F irst, Dr.A nna Vulpetti (Novartis) presented the development of small-molecule inhibitors for factor D, an S1 serine protease involved in aw ide range of diversec linical disorders. Combining scaffolds from both fragment-based screening and structure-based protein design, her team obtained al igand capable of selectively binding to factor Dt hat has shown activity in the nanomolar range (K d : 0.006 mm)i nadirect binding assay using surface plasmon resonance spectroscopy.…”

“On‐Water” Palladium‐Catalyzed Tandem Cyclization Reaction for the Synthesis of Biologically Relevant 4‐Arylquinazolines

“…To furtheri llustrate the synthetic utility,t his method was then applied to the synthesis of N11 ( Figure 1), which is a highly potent and selectiveP I3Kd inhibitor developed by Novartis for the treatment of inflammatory diseases. [10] Under the slightly modified reaction conditions, the keyi ntermediate 4e was efficiently synthesized in 67 %y ield on ag ram scale. In contrast, Compound 4e had been previously synthesized in an overall yield of 48 %, whichi nvolvedf our consecutive steps and harsh reaction conditions.…”