Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α 2A -adrenergic receptor (α 2A AR), seeking new α 2A AR agonists chemotypes that lack the sedation conferred by known α 2A AR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G i and G o signaling. Experimental structures of α 2A AR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit ‘9087 [mean effective concentration (EC 50 ) of 52 nanomolar] and two analogs, ‘7075 and PS75 (EC 50 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

A number of 3-acylamino-6-polyfluoroalkyl-2H-pyran-2-ones 3 were synthesized from b-alkoxyvinyl polyfluoroalkyl ketones 1 and N-acylglycines 2 in acetic anhydride in high yield. The reactions of trifluoromethyl-containing 2H-pyran-2-one 3b with Oand N-nucleophiles were studied and 3-N-benzoylamino-6-hydroxy-6-trifluoromethyl-5,6-dihydro-2H-pyran-2-one (13), 3-Nbenzoylamino-6-hydroxy-6-trifluoromethyl-5,6-dihydro-2H-pyridin-2-one (14a), and N-and O-substituted 3-(N-benzoylamino)-6-trifluoromethyl-2H-pyridin-2-ones (15c,e, and 16) were synthesized.

Addition reactions of perfluoroalkyl radicals to ordinary or polyfluorinated alkenes have been frequently used to synthesize perfluoroalkylated organic compounds. Here ethyl/methyl 2-bromo-2,2-difluoroacetate, diethyl (bromodifluoromethyl)phosphonate, [(bromodifluoromethyl)sulfonyl]benzene, and ethyl 2-bromo-2-fluoroacetate were involved in Na2S2O4-mediated radical additions to vinyl ethers in the presence of alcohols to give difluoro or monofluoroacetyl-substituted acetals or corresponding difluoromethylphosphonate- and (difluoromethylphenyl)sulfonyl-substituted alkyl acetals. This methodology has also been applied as a key step in the synthesis of hitherto unknown 3,3-difluoro-GABA, completing the series of isomeric difluoro GABAs. Comparison of the pKa values of 3-fluoro- and 3,3-difluoro-GABA with that of the fluorine free parent compound showed that introduction of each fluorine lead to acidification of both the amino and the carboxyl functions by approximately one unit.

The hitherto unreported reactions of β-alkoxyvinyl polyfluoroalkyl ketones with ethyl isocyanoacetate and equimolar amounts of potassium-tert-butoxide proceeded mainly in the β-position of the α,β-unsaturated ketones in cases of α-nonsubstituted 1a–e and α-methyl substituted ketones 1g–j. Other α- or β-substituted ketones 1f,k–o gave mainly products 4 of initial attack at the carbonyl carbon. Depending on the solvent, the major products of β-attack do exist in different tautomeric forms. Generally the openchain enol tautomers 5 predominate in the polar DMSO-d(6), while the cyclic γ-hemiaminals 8 are the major tautomers in the less polar CDCl(3). Acid treatment of the latter compounds 8 led to the hitherto unknown ethyl 5-polyfluoroalkyl-pyrrole-2-carboxylates 11 by elimination of formic acid. Catalytic hydrogenation of pyrrole 11a was used for the synthesis of earlier unknown 5-trifluoromethyl proline 16.