ABSTRACT
The approvals of idelalisib and duvelisib have validated PI3Kδ inhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors with excellent isoform and kinome selectivity; however, they had high projected human doses. Improved ligand contacts gave potency enhancements, while replacement of metabolic liabilities led to extended half-lives in preclinical species, affording PI3Kδ inhibitors with low once-daily predicted human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice with 30 and 100 mg/kg/day of 3c (MSD-496486311) led to a 70% reduction in Foxp3-expressing regulatory T cells as observed through bioluminescence imaging with luciferin, consistent with the role of PI3K/AKT signaling in Treg cell proliferation. As a model for allergic rhinitis and asthma, treatment of ovalbumin-challenged Brown Norway rats with 0.3 to 30 mg/kg/day of 3c gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation eosinophil cell count.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/chemistry , Immunologic Factors/chemistry , Pyrrolidines/chemistry , Animals , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , B-Lymphocytes/cytology , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Binding Sites , Class I Phosphatidylinositol 3-Kinases/metabolism , Disease Models, Animal , Dogs , Half-Life , Humans , Immunologic Factors/metabolism , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Lectins, C-Type/metabolism , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Proto-Oncogene Proteins c-akt/metabolism , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Rats , Rats, Wistar , Rhinitis, Allergic/drug therapy , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.
Subject(s)
Class Ia Phosphatidylinositol 3-Kinase/metabolism , Protein Kinase Inhibitors/pharmacology , Purines/pharmacology , Pyrrolidines/pharmacology , Animals , Dogs , Drug Design , HeLa Cells , Humans , Male , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/toxicity , Purines/chemical synthesis , Purines/toxicity , Pyrrolidines/chemical synthesis , Pyrrolidines/toxicity , Rats, WistarABSTRACT
Severe burns induce pathophysiologic problems, among them catabolism of lean mass, leading to protracted hospitalization and prolonged recovery. Oxandrolone is an anabolic agent shown to decrease lean mass catabolism and improve wound healing in the severely burned patients. We enrolled 81 adult subjects with burns 20% to 60% TBSA in a multicenter trial testing the effects of oxandrolone on length of hospital stay. Subjects were randomized between oxandrolone 10 mg every 12 hours or placebo. The study was stopped halfway through projected enrollment because of a significant difference between groups found on planned interim analysis. We found that length of stay was shorter in the oxandrolone group (31.6 +/- 3.1 days) than placebo (43.3 +/- 5.3 days; P < .05). This difference strengthened when deaths were excluded and hospital stay was indexed to burn size (1.24 +/- 0.15 days/% TBSA burned vs 0.87 +/- 0.05 days/% TBSA burned, P < .05). We conclude that treatment using oxandrolone should be considered for use in the severely burned while hepatic transaminases are monitored.
