Guixue Yu

A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice

It is well established that melanocortins are peptides that have potent anti‐inflammatory activity. Recent research has focused on understanding which of the known melanocortin receptors mediates the anti‐inflammatory actions of the melanocortins. The aim of this study was to assess the anti‐inflammatory activity of a synthetic MC‐1R agonist. BMS‐470539 is a potent, selective, full agonist of human and murine MC‐1R with EC50 values in a cAMP accumulation assay of 16.8 and 11.6 nM, respectively. BMS‐470539 dose‐dependently inhibited TNF‐α‐induced activation of a NF‐κB transcriptional reporter in human melanoma cells, which endogenously express MC‐1R. In vivo studies with BMS‐470539 demonstrated that subcutaneous administration of BMS‐470539 resulted in a dose‐dependent inhibition of LPS‐induced TNF‐α production in BALB/c mice. In this model, the compound had an ED50 of approximately 10 μmol/kg and a pharmacodynamic half‐life of ∼8 h. Pharmacokinetic analysis of the compound indicated that the compound had a t1/2 of 1.7 h. In a model of lung inflammation, administration of 15 μmol/kg BMS‐470539 resulted in a 45% reduction in LPS‐induced leukocyte infiltration (an infiltrate comprised primarily of neutrophils). The compound was also effective in a model of delayed‐type hypersensitivity, reducing paw swelling by 59%, comparable with that seen with 5 mg/kg dexamethasone. These studies demonstrate that a selective small molecule agonist of the melanocortin‐1 receptor is a potent anti‐inflammatory agent in vivo and provides compelling evidence for the involvement of this receptor in the modulation of inflammation.

Synthesis of fused pyridopyrrolidine dione derivatives using hetero Diels–Alder reactions

Abstract Hetero Diels–Alder reactions of heteroaromatic amidines and maleimide afforded novel fused pyridopyrrolidine dione scaffolds in moderate to good yields under mild conditions.

Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

A mild and efficient method for aromatic chlorination of electron-rich arylalkyl amines

Abstract Sulfuryl chloride was used to chlorinate electron-rich arylalkyl amines in a mild and efficient one-pot transformation with simple product isolation via precipitation. Protection of the amine was not needed.