α₂ Adrenoceptor Agonists as Potential Analgesic Agents. 3. Imidazolylmethylthiophenes

Abstract

A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the alpha(2) adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the alpha(2D) adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED(50) doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.

α2‐Agonists as analgesic agents

“…Moreover, the substitution of the imidazole ring with other nuclei results in a dramatic loss of binding affinity and analgesic activity, demonstrating the essentiality of this portion of the molecule. A series of compounds of particular interest is represented by imidazolylalkyl-2 and 3-thiophene derivatives [162][163][164] (compounds 7-16, Figs. 2 and 3), which exhibit an increased potency with respect to the previous series.…”

Five‐Membered Heterocycles: 1,3‐Azoles

“…The generated imidazolylmagnesium halide has been employed in addition reactions to carbonyl compounds for the preparation, for example, of ligands for the a 2D adrenergic receptor [218], sugar-mimic glycosidase inhibitors [219] or C-nucleosides [220]. It has also been used in acylation reactions with esters in the synthesis of pilocarpine analogues [221] or with Weinreb amides such as 145 (Scheme 10.67) [222].…”

Rh-Catalyzed Highly Enantioselective Synthesis of Aliphatic Sulfonyl Fluorides

“…Di(hetero)arylalkanes are ubiquitous and important structures as building blocks in drug discovery (Figure 2) (Zhou et al., 2013, He et al., 2018, Graffner-Nordberg et al., 2001, Boyd et al., 2001, Hsin et al., 2002, Hills et al., 1998, Silva et al., 1999, Malhotra et al., 2009, Hu et al., 2010, Pathak et al., 2010, Ameen and Snape, 2013). To accelerate the discovery of new covalent drug candidates, we plan to build diversified compound libraries bearing both di(hetero)arylalkane and sulfonyl fluoride functionalities (Schreiber, 2000, O’Connor et al., 2012, Nadin et al., 2012).…”