Identification of a novel series of benzimidazoles as potent and selective antagonists of the human melanocortin-4 receptor.

A novel series of benzimidazoles was identified and optimized, leading to the discovery of potent and selective antagonists of the human melanocortin-4 receptor. In addition, compound 5i was shown to cross the blood-brain barrier after intravenous dosing in rats.

Identification of potent non-peptide somatostatin antagonists with sst(3) selectivity.

Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogues were prepared, and their binding affinities to the five human somatostatin receptor subtypes (sst(1-5)) were determined. Imidazolyl derivatives 2 were found to bind with moderate affinity but with high selectivity to the sst(3) receptor subtype. Further modifications of these structures led to a more potent class of ligands, the tetrahydro-beta-carboline derivatives 4.

Novel non-peptide ligands for the somatostatin sst3 receptor.

A series of imidazole derivatives has been prepared using high throughput parallel synthesis. Several compounds showed high affinity (Ki in 10(-6)-10(-8) M range) and selectivity at recombinant human somatostatin receptor subtype 3 (hsst3).

Synthesis of substituted imidazopyrazines as ligands for the human somatostatin receptor subtype 5.

A new preparation of trisubstituted imidazopyrazines and dihydroimidazopyrazines via parallel synthesis using aminoacids and bromoketones resulted in the discovery of non-peptidic sst5 selective agonists.

Synthesis of peptidomimics through sugar-based scaffolds.

Poor oral bioavailability, low metabolic stability towards proteolysis and rapid excretion via both liver and kidneys displayed by innumerable peptides of potential therapeutic value has generated an intensive search for peptidomimics (1-2). A possible approach of such nonpeptidal peptidomimics is to replace the peptide by a scaffold that distributes in the space the peptidal side chains of amino acids essential for biological activity and mimics the bioactive conformation of the peptide.