Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor.

The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.

Analysis of volatile organic compounds in mainstream cigarette smoke.

Mainstream cigarette smoke is a complex aerosol containing more than 4400 chemicals. The proliferation of new brands has necessitated development of faster and more reliable methods capable of analyzing a wide range of compounds in cigarette smoke. Although the International Agency for Research on Cancer has classified whole cigarette smoke as a human carcinogen, many of the individual chemicals are themselves highly biologically active as carcinogens, teratogens, or have implications for cardiovascular disease. Among these chemicals are many volatile organic compounds (VOCs), e.g., benzene, ethylbenzene, and styrene. To analyze VOCs in mainstream cigarette smoke, we developed a novel headspace collection technique using polyvinylfluoride bags for sample collection followed by cannula transfer to evacuated standard 20-mL auto sampler vials. Coupling collection of the vapor-phase cigarette smoke with automated analysis by solid-phase microextraction and gas chromatography/mass spectrometry enabled us to routinely quantify selected VOCs in mainstream cigarette smoke. This technique has similar reproducibility to previous cold trap and impinger collection methods with significantly higher sample throughput and virtually no solvent waste. In this report we demonstrate the method's analytical capabilities by quantitatively analyzing 13 selected VOCs in mainstream cigarette smoke from top-selling domestic brands.