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.

Two introduced crocodile species had changed reproductive characteristics in China.

The purpose of this study was to study the reproductive characteristics of the Nile crocodile and Siamese crocodiles after introduction into China since the time this occurred near the end of the last century. The data for the eggs and young crocodiles (recently hatched crocodiles) of two introduced species were collected at a Sanya crocodile breeding farm in Hainan. The characteristic variables of crocodile eggs were statistically analyzed, and the results indicated that: egg mass of the Nile and Siamese crocodile was significantly correlated with the egg length and width.

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.

Mitochondrial Cyclophilin D as a Potential Therapeutic Target for Ischemia-Induced Facial Palsy in Rats.

Many studies have demonstrated that ischemia could induce facial nerve (FN) injury. However, there is a lack of a suitable animal model for FN injury study and thus little knowledge is available about the precise mechanism for FN injury. The aims of this study were to establish a reliable FN injury model induced by blocking the petrosal artery and to investigate whether dysfunctional interaction between cyclophilin D (CypD) and mitochondrial permeability transition pore (MPTP) can mediate cell dysfunction in ischemic FN injury.

Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 2: non-symmetric inhibitors with potent activity against genotype 1a and 1b.

The discovery of non-symmetric thienoimidazole-containing HCV NS5A inhibitors is described. The inhibitors herein reported display high potencies against both genotype 1a and 1b. In this follow-up manuscript, we discuss the importance of the linker aromaticity to achieve high potency, particularly against genotype 1a.

Synthesis and evaluation of NS5A inhibitors containing diverse heteroaromatic cores.

Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics.

Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors.

The discovery of potent thienoimidazole-based HCV NS5A inhibitors is herein reported. A novel method to access the thienoimidazole [5,5]-bicyclic system is disclosed. This method gave access to a common key intermediate (6) that was engaged in Suzuki or Sonogashira reactions with coupling partners bearing different linkers.

VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia.

In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K(i) values of <1 nM and a cellular IC(50) between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured.

Design, synthesis, and evaluation of a novel dual FMS-like tyrosine kinase 3/stem cell factor receptor (FLT3/c-KIT) inhibitor for the treatment of acute myelogenous leukemia.

A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading to dose-dependent cell death in acute myelogenous leukemia (AML) patient blast samples. Ultimately, the AML patient blast data defined the preferred target profile as we designed and evaluated a set of FLT3 selective and FLT3/c-KIT dual molecules.

Contrast detection learning improves visual contrast sensitivity of cat.

Psychological studies on human subjects show that contrast detection learning promote learner's sensitivity to visual stimulus contrast. The underlying neural mechanisms remain unknown. In this study, three cats (Felis catus) were trained to perform monocularly a contrast detection task by two-alternative forced choice method.

Perceptual learning improves contrast sensitivity of V1 neurons in cats.

Background: Perceptual learning has been documented in adult humans over a wide range of tasks. Although the often-observed specificity of learning is generally interpreted as evidence for training-induced plasticity in early cortical areas, physiological evidence for training-induced changes in early visual cortical areas is modest, despite reports of learning-induced changes of cortical activities in fMRI studies. To reveal the physiological bases of perceptual learning, we combined psychophysical measurements with extracellular single-unit recording under anesthetized preparations and examined the effects of training in grating orientation identification on both perceptual and neuronal contrast sensitivity functions of cats.

Bifunctional ligands that target cells displaying the alpha v beta3 integrin.

Strategies to eliminate tumor cells have long been sought. We envisioned that a small molecule could be used to decorate the offending cells with immunogenic carbohydrates and evoke an immune response. To this end, we describe the synthesis of bifunctional ligands possessing two functional motifs: one binds a cell-surface protein and the other binds a naturally occurring human antibody.

Lipase Catalyzed Biosynthesis of Lactones.

Lactones derived from hydroxy fatty acids have many applications. Compared to conventional chemical synthesis, lipases catalyzed synthesis of lactones is simple, mild and highly productive. The effects of hydroxy fatty acid chain length, solvents, lipase type and steric factor on the yield and on the distribution of the produced lactones were investigated.