Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors

Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, <b>1</b> (AM-8508) and <b>2</b> (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inbibitors <b>1</b> and <b>2</b> led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH

Discovery and in Vivo Evaluation of Dual PI3Kβ/δ Inhibitors

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue <b>63</b> was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue <b>63</b> was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases

Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2‑((1<i>S</i>)‑1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro‑<i>N</i>‑methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2‑((1<i>S</i>)‑1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro‑<i>N</i>‑methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430)

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, <b>4</b>, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, <b>6a</b> (AM-0687) and <b>7</b> (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of <b>6a</b> and <b>7</b> in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either <b>6a</b> or <b>7</b> resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development

Discovery and in Vivo Evaluation of (<i>S</i>)‑<i>N</i>‑(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)‑9<i>H</i>‑purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of <b>1</b> (AMG319), a compound with an IC₅₀ of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation