Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders.

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.

Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors.

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.

Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kδ inhibitors.

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.

[Effect of combined therapy with Chinese drug and narrow broad ultraviolet B on Bcl-2, caspase-3 and survivin in skin lesion with psoriasis vulgaris].

OBJECTIVE: To reveal the possible role of combined therapy with Chinese drug and narrow broad ultraviolet B (NB-UVB) on keratinocytes apoptosis in skin lesion of psoriasis vulgaris (PV). METHODS: Skin samples were taken from 20 healthy subjects and 30 PV patients before and after they received the combined therapy for 8 weeks. SP immunohistochemical method was used to detect the expressions of Bcl-2, Caspase-3 and survivin in the samples. RESULTS: As compared with those in the normal skin, expression of Bcl-2 in PV skin was significantly lower (7.50 +/- 2.01 vs. 12.65 +/- 2.83), while expression of Caspase-3 (21.73 +/- 3.70 vs. 8.55 +/- 2.16), and survivin (23.90 +/- 2.82 vs. 7.06 +/- 1.96) were higher (all P < 0.01). After treatment, in skin of PV, Bcl-2 expression increased to 13.63 +/- 2.14, Caspase-3 and survivin decreased to 11.70 +/- 2.44 and 12.46 +/- 1.80, respectively (all P < 0.01), showing a normalizing trend. Moreover, patients' psoriasis area and severity index (PASI) score decreased from 14.24 +/- 3.42 before treatment to 3.52 +/- 1.07 after treatment (P < 0.01). CONCLUSION: The curing effect of the combined therapy with Chinese drug and NB-UVB in treating PV is possibly realized by way of regulating Bcl-2, Caspase-3 and survivin expressions to adjust keratinocyte apoptosis.