Far Away from Flatland. Synthesis and Molecular Structure of Dihetera[3.3.n]propellanes and Trihetera[3.3.n]propellanes: Advanced Analogues of Morpholine/Piperazine.

An approach to di- and trihetera[3.3.n]propellanes (n = 2-4 ), advanced morpholine and piperazine analogues, is developed. The key step of the reaction sequence included a [3 + 2] cycloaddition reaction of unsaturated vicinal dicarboxylic acid derivatives and in situ generated azomethine ylide resulting in the formation of the pyrrolidine ring. One more heteroaliphatic ring (i.e., pyrrolidine or tetrahydrofuran) was annelated by nucleophilic cyclization of the appropriate 1,4-dielectrophilic intermediates. There were 11 examples of the title products obtained in 3-5 steps on a multigram scale with 10-72% overall yields. Additionally, molecular structures of homologous dihetera[3.3.n]propellanes, analogues of morpholine, were obtained from X-ray diffraction studies and analyzed using exit vector plots (EVPs). It was shown that the scaffolds obtained are somewhat larger as compared to the parent morpholine and bicyclic 3-oxa-7-azabicyclo[3.3.0]octane. Moreover, despite very similar chemical structures, they provide a very distinct spatial position of heteroatoms, which is clearly seen from the conformation adopted by a formal eight-membered ring including both N and O atoms (i.e., crown, boat-chair, twist chair-chair, and boat-boat for the oxaza[3.3.2]-, -[3.3.3]-, -[4.3.3]propellanes, and 3-oxa-7-azabicyclo[3.3.0]octane, respectively).

Discovery, Synthesis, and In Vitro Characterization of 2,3 Derivatives of 4,5,6,7-Tetrahydro-Benzothiophene as Potent Modulators of Retinoic Acid Receptor-Related Orphan Receptor γt.

Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor that is expressed in a variety of tissues and is a potential drug target for the treatment of inflammatory and auto-immune diseases, metabolic diseases, and resistant cancer types. We herein report the discovery of 2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene modulators of RORγt. We also report the solubility in acidic/neutral pH, mouse/human/dog/rat microsomal stability, Caco-2, and MDR1-MDCKII permeabilities of a set of these derivatives. For this group of modulators, inverse agonism by steric clashes and push-pull mechanisms induce greater instability to protein conformation compared to agonist lock hydration. Independent of the two mechanisms, we observed a basal modulatory activity of the tested 2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene toward RORγt due to the interactions with the Cys320-Glu326 and Arg364-Phe377 hydrophilic regions. The drug discovery approach reported in the current study can be employed to discover modulators of nuclear receptors and other globular protein targets.

Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists.

A number of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines were prepared and their 5-HT6 receptor binding affinity and ability to inhibit the functional cellular responses to serotonin were evaluated. 3-[(3-chlorophenyl)sulfonyl]-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{5,26} appeared to be the most active in a functional assay (IC50=29.0 nM) and 3-(phenylsulfonyl)-N-(2-thienylmethyl) thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{1,28} demonstrated the greatest affinity in a 5-HT6 receptor radioligand binding assay (Ki=1.7 nM). A screening of 5-HT2A and 5-HT2B receptor affinity revealed that 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines are highly selective 5-HT6 receptor ligands.

Solution phase parallel synthesis of substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines: selective serotonin 5-HT(6) receptor antagonists.

Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure with a 5-HT(6) receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive binding. We have found highly active and selective 5-HT(6)R antagonists. The most active 5-HT(6)R antagonists have IC(50) <100 nM in a functional assay, and K(i) <10 nM in a binding assay, which is 100 times higher than the activity with respect to other serotonin receptors.