The main disadvantages of peptide pharmaceuticals are their rapid degradation and excretion, their low hydrophilicity, and low shelf lifes. These bottlenecks can be circumvented by acylation with fatty acids (lipidation) or polyethylene glycol (PEGylation). Here, we describe the modification of a human pancreatic polypeptide analogue specific for the human (h)Y(2) and hY(4) receptor with PEGs of different size and palmitic acid. Receptor specificity was demonstrated by competitive binding studies. Modifications had only a small influence on binding affinities and no influence on secondary structure. Both modifications improved pharmacokinetic properties of the hPP analogue in vivo and in vitro, however, lipidation showed a greater resistance to degradation and excretion than PEGylation. Furthermore, the lipidated peptide is taken up and degraded solely by the liver but not the kidneys. Lipidation resulted in prolonged action of the hPP analogue in respect of reducing food intake in mice after subcutaneous administration. Therefore, the lipidated hPP analogue could constitute a potential new therapeutic agent against obesity.

Aim Cannabinoid receptor type 1 (CB1) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 was studied in humans. Methods This was a double‐blind, randomized, placebo‐controlled, crossover study. On occasions 1–4, 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK−PD modelling. Results The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half‐life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [−26.70% [90% confidence interval (CI) −40.9, −12.6%]; −7.10%, (90%CI −18.1, 5.3%); −7.30%, (90% CI −11.5%, −3.0%) respectively] and TM38837 500 mg [−22.10% (90% CI −34.9, −9.4%); −12.20% (90% CI −21.6%, −1.7%); −8.90% (90% CI −12.8%, −5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. Conclusions Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.

Condensations between the dianion 1 derived from 1-(N-butoxycarbonylamino)-1H-benzotriazole and silyloxysalicylaldehydes 10 give excellent yields of the expected adducts 11. While attempts to remove the N-Boc function were unsuccessful, desilylation and hydrogenolysis delivered the hydroxybenzyl derivative 14 which could be efficiently deprotected to give the amine 15. This then underwent smooth decomposition to the benzyne 16, upon exposure to N-iodosuccinimide, and intramolecular trapping by the phenol group, with incorporation of iodine, to give the iodoxanthene 17. A more efficient protocol featured condensation of dianion 1 with 2-(benzyloxy)aryl aldehydes; hydrogenolysis of the initial products 19 and 22a served both to deprotect the phenol function and to effect hydrogenolysis of the benzylic alcohol group. A final acidic deprotection and exposure to N-iodosuccinimide delivered good yields of the iodoxanthenes 21 and 23, demonstrating for the first time a viable method for the intramolecular trapping of benzynes by phenolic groups.

Novel 6-acylamino-2-aminoquinoline melanin-concentrating hormone 1 receptor (MCH1R) antagonists were identified by sequential in silico screening with 3D pharmacophore models derived from a series of benzamide antagonists. The structure-activity relationship exploration by synthesis of analogues found structural demands around the western part of the compounds to be quite specific, whereas much structural freedom was found in the eastern part. While these compounds in general suffered from poor solubility properties, the 4-trifluoromethoxyphenoxyacetamide western appendage provided a favorable combination of activity and solubility properties. The amine in the eastern appendage, originally required by the pharmacophore model and believed to interact with Asp123 in transmembrane 3 of MCH1R, could be removed without diminishing affinity or functional activity of the compounds. Docking studies suggested that the Asp123 interacts preferentially with the nitrogen of the central quinoline. Synthesis and testing of specific analogues supported our revised binding mode hypothesis.

Condensation of dianion 2 derived from aminobenzotriazole