Discovery of a Novel Series of Potent and Selective Alkynylthiazole-Derived PI3Kγ Inhibitors.

Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that control a wide variety of cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. PI3Kγ plays a critical role in mediating leukocyte chemotaxis as well as mast cell degranulation, making it a potentially interesting target for autoimmune and inflammatory diseases. We previously disclosed a novel series of PI3Kγ inhibitors derived from a benzothiazole core. The truncation of the benzothiazole core led to the discovery of a structurally diverse alkynyl thiazole series which displayed high PI3Kγ potency and subtype selectivity. Further medicinal chemistry optimization of the alkynyl thiazole series led to identification of compounds such as 14 and 32, highly potent, subtype selective, and CNS penetrant PI3Kγ inhibitors. Compound 14 showed robust inhibition of PI3Kγ mediated neutrophil migration in vivo.

2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase γ.

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.

Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases.

While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.

Versatile and facile synthesis of diverse semisynthetic tetracycline derivatives via Pd-catalyzed reactions.

A diverse collection of tetracycline derivatives has been synthesized utilizing Heck, Suzuki, and other palladium-coupling reactions via tetracycline arenediazonium and iodoarene salts. Large numbers of tetracyclines are now possible via these reactions, including numerous upper periphery derivatives of doxycycline, minocycline, sancycline, and methacycline modified at positions C7, C9, and C6-C13 on the tetracycline naphthacene ring. Application of palladium-coupling reactions to the tetracyclines has yielded new tetracycline classes with differing structural attributes, greatly increasing the structural diversity of this family of antibiotics, one of the last of the early antibiotic families to be expanded by organic and medicinal chemistry.