From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome

Selective inhibitors of phosphoinositide 3-kinase delta are of interest for the treatment of inflammatory diseases. Initial optimization of a 3-substituted indazole hit compound targeting the kinase PIM1 focused on improving selectivity over GSK3β through consideration of differences in the ATP binding pockets. Continued kinase cross-screening showed PI3Kδ activity in a series of 4,6-disubstituted indazole compounds, and subsequent structure–activity relationship exploration led to the discovery of an indole-containing lead compound as a potent PI3Kδ inhibitor with selectivity over the other PI3K isoforms

Structure Activity Relationships of α_v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents

Antagonism of α_vβ₆ is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an α_vβ₃ antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved α_vβ₆ activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds <b>33S</b> and <b>43E1</b> are pan α_v antagonists having <i>ca.</i> 100 nM potency against α_vβ_3, α_vβ_5, α_vβ₆, and α_vβ₈ in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC₅₀ values between the integrins in question) for α_vβ₃ and α_vβ₅

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3‑Kinase δ for the Treatment of Respiratory Disease

Optimization of lead compound <b>1</b>, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates <b>2</b> (GSK2269557) and <b>3</b> (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds <b>2</b> and <b>3</b> are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation

Correction to Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAP-K2) as an Antiinflammatory Target: Discovery and in Vivo Activity of Selective Pyrazolo[1,5‑<i>a</i>]pyrimidine Inhibitors Using a Focused Library and Structure-Based Optimization Approach

Correction to Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAP-K2) as an Antiinflammatory Target: Discovery and in Vivo Activity of Selective Pyrazolo[1,5‑<i>a</i>]pyrimidine Inhibitors Using a Focused Library and Structure-Based Optimization Approac

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3‑Kinase δ for the Treatment of Respiratory Disease

Optimization of lead compound <b>1</b>, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates <b>2</b> (GSK2269557) and <b>3</b> (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds <b>2</b> and <b>3</b> are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation