Azole derivatives as histamine H3 receptor antagonists, part I: thiazol-2-yl ethers.

Most human histamine H(3) receptor (hH(3)R) antagonists follow a general structural blueprint, containing a basic moiety linked by a spacer to a substituted core element. In this investigation the acceptance of thiazol-2-yl ether moieties in the core region is proved with some ether derivatives showing hH(3)R binding affinities in the nanomolar concentration range. A diversity of structural motifs is used as substituents to enhance the in vitro hH(3)R binding affinity.

Azole derivatives as histamine H3 receptor antagonists, part 2: C-C and C-S coupled heterocycles.

With a small series of compounds we demonstrated the variability in the core region of the human histamine H(3) receptor (hH(3)R) antagonist structural blueprint by introducing polar azole groups (oxazole, oxadiazole, thiazole and triazole). Additional variations achieved by coupling different residues to the heterocyclic core structure led to further optimisation of in vitro receptor binding of the novel azole derivatives.

First metal-containing histamine H3 receptor ligands.

Iron-containing ligands targeting the human histamine H(3) receptor (hH(3)R) were prepared. The compounds contain ferrocene sandwich complexes coupled via different linkers to a basic hH(3)R antagonist/inverse agonist pharmacophore. In a click chemistry approach, a triazole was successfully inserted as a new linking element.

Acidic elements in histamine H(3) receptor antagonists.

Antagonists of the human histamine H(3) receptor (hH(3)R) often contain a second basic moiety, which is well known to boost affinity on this histamine receptor subtype. Here, we prepared compounds with acidic moieties of different pK(a) values to figure out that the hH(3)R tolerates these functionalities when added to a common pharmacophore blueprint. Depending on the acidic, electronic and steric features the designed ligands showed hH(3)R affinities in the nanomolar concentration range.