Effect of Yb3+ concentration on upconversion luminescence and optical thermometry sensitivity of La2MoO6: Yb3+, Er3+ phosphors.

La2MoO6:Yb3+,Er3+ upconversion (UC) micro-crystals with a tetragonal structure were fabricated through a modified sol-gel method. The samples are found to be spherical in shape with a diameter of about 300 nm. Upon excitation of 980 nm light, the UC emission spectra of the phosphors exhibit green and red bands corresponding to the characteristic transitions of Er3+ ions. As Yb3+ concentration rises, the green emission intensity increases and reaches the maximum at 2.0% Yb3+ content, while the ratio of green/red emission intensities (IG/IR) declines monotonically. Temperature sensing capability was studied employing the fluorescent intensity ratio technique from the thermally coupled levels 2H11/2 and 4S3/2 of Er3+ in temperature range of 293∼533 K. It is interesting to find that Yb3+ concentration has influence on the absolute sensitivity SA, while the relative sensitivity SR is almost independent of Yb3+ content. Furthermore, excellent thermal stability and high temperature sensitivity is also demonstrated in the 2.0% Yb3+-doped sample with the obtained maximum SA and SR as high as 0.008K-1 and 1.093%K-1, respectively. The experimental results indicate that Yb3+/Er3+ co-doped La2MoO6 phosphors can be excellent candidates for temperature sensing applications.

Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1.

Cellular protein synthesis is initiated with methionine in eukaryotes with few exceptions. Methionine aminopeptidases (MetAPs) which catalyze the process of N-terminal methionine excision are essential for all organisms. In mammals, type 2 MetAP (MetAP2) is known to be important for angiogenesis, while type 1 MetAP (MetAP1) has been shown to play a pivotal role in cell proliferation. Our previous high-throughput screening of a commercial compound library uncovered a novel class of inhibitors for both human MetAP1 (HsMetAP1) and human MetAP2 (HsMetAP2). This class of inhibitors contains a pyridinylpyrimidine core. To understand the structure-activity relationship (SAR) and to search for analogues of 2 with greater potency and higher HsMetAP1-selectivity, a total of 58 analogues were acquired through either commercial source or by in-house synthesis and their inhibitory activities against HsMetAP1 and HsMetAP2 were determined. Through this systematic medicinal chemistry analysis, we have identified (1) 5-chloro-6-methyl-2-pyridin-2-ylpyrimidine as the minimum element for the inhibition of HsMetAP1; (2) 5'-chloro as the favored substituent on the pyridine ring for the enhanced potency against HsMetAP1; and (3) long C4 side chains as the essentials for higher HsMetAP1-selectivity. At the end of our SAR campaign, 25b, 25c, 26d and 30a-30c are among the most selective and potent inhibitors of purified HsMetAP1 reported to date. In addition, we also performed crystallographic analysis of one representative inhibitor (26d) in complex with N-terminally truncated HsMetAP1.

Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is becoming the most predominant burden of chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, can develop into cirrhosis and hepatocellular cancer. Unfortunately, current options for therapeutic treatment of NASH are very limited. Among multiple pathways in NASH, farnesoid X receptor (FXR), a nuclear bile acid receptor, is well-recognized as an important effective target. Here we report the synthesis and characterization of compound HEC96719 a novel tricyclic FXR agonist based on a prior high-affinity nonsteroidal molecule GW4064. HEC96719 exhibits excellent potency superior to GW4064 and obeticholic acid in in vitro and in vivo assays of FXR activation. It also shows higher FXR selectivity and more favorable tissue distribution dominantly in liver and intestine. Preclinical data on pharmacokinetic properties, efficacy, and safety profiles overall indicate that HEC96719 is a promising drug candidate for NASH treatment.

The development of HEC-866 and its analogues for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a typical survival time between three to five years. Two drugs, pirfenidone and nintedanib have been approved for the treatment of IPF, but they have limited efficacy. Thus, the development of new drugs to treat IPF is an urgent medical need. In this paper we report the discovery of a series of orally active pyrimidin-4(3H)-one analogs which exhibit potent activity in in vitro assays. Among them, HEC-866 showed promising efficacy in rat IPF models. Since HEC-866 also had good oral bioavailability, a long half-life and favorable long-term safety profiles, it was selected for further clinical evaluation.

CuI/DMPAO-catalyzed N-arylation of acyclic secondary amines.

DMPAO has been found to be a powerful ligand to enable copper-catalyzed coupling of aryl halides with aliphatic acyclic secondary amines take place under relatively mild conditions, and coupling of aryl halides with primary amines and cyclic secondary amines proceeds at low catalyst loading.