Muscle atrophy and cachexia are common comorbidities among patients suffering from cancer, chronic obstructive pulmonary disease, and several other chronic diseases. The peptide hormone ghrelin exerts pleiotropic effects including the stimulation of growth hormone secretion and subsequent increase of insulin-like growth factor-1 levels, an important mediator of muscle growth and repair. Ghrelin also acts on inflammation, appetite, and adipogenesis and therefore has been considered a promising therapeutic target for catabolic conditions. We previously reported on the synthesis and properties of an indane based series of ghrelin receptor full agonists which led to a sustained increase of insulin-like growth factor-1 in a dog pharmacodynamic study. Herein we report on the identification of a series of pyrrolidine or piperidine based full agonists and attempted optimization to give compounds with profiles suitable for progression as clinical candidates.

A randomised, placebo-controlled, double blind single-dose cross-over study was arranged to investigate possible interactions between zopiclone (7.5 mg) and two widely used benzodiazepine (BZD) anxiolytics diazepam (5 mg) and lorazepam (1 mg) during the elimination phase of drugs. Psychomotor performance was tested before and 1, 6, 8, 12 and 24 hr after the drug administration. Simultaneously, blood samples were drawn for determination of plasma drug concentrations. The elimination of each compound was not altered by coadministration of other drugs. As expected, one hour after drug ingestion, psychomotor performance was impaired. The coadministration of drugs increased the effect. During the elimination phase, 6 and 8 hr after the drug intake, only zopiclone and lorazepam in combination slightly impaired performance as compared with the pretreatment levels, but there was no difference as compared with placebo. Adverse events after active treatments were not significantly different from those after placebo. At the recommended dose of 7.5 mg, zopiclone does not alter the elimination pharmacokinetics of the BZD anxiolytics diazepam (5mg) and lorazepam (1 mg), and neither is the elimination of zopiclone affected by these BZDs. Due to the rapid elimination of zopiclone, the increase in sedation seen after concurrent administration with BZDs is of short duration.

The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14-labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol. [(14) C]AZD5069 was labelled in the pyrimidine ring from [(14) C]thiourea in an overall radiochemical yield of 18%. In addition, a synthetic route to the major metabolite of AZD5069 was developed. The synthesis of this metabolite was achieved from AZD5069 using a chemoselective Lindgren-Pinnick reaction in order to minimize oxidation of the sulphide group.