2006Carboxylic acids Q 0420Synthesis and Activity of Small Molecule GPR40 Agonists. -A variety of novel compounds, e.g. (VI) and (VII), that activate GPR40 at low nanomolar concentrations, is identified. (VI) behaves as a potent, full agonist at the GPR40 receptor with a pEC50 = 7.91. The acid itself is not critical for activity but elicits a higher agonistic response than that observed with carboxamide replacements (some yields not given).-(GARRIDO, D. M.; CORBETT, D. F.; DWORNIK, K. A.; GOETZ, A. S.; LITTLETON, T. R.; MCKEOWN, S. C.; MILLS, W. Y.; SMALLEY, T. L. J.; BRISCOE, C. P.; PEAT*, A.

A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent in vitro inhibition of HCV replication (EC50 < 10 nM), direct binding to purified NS4B protein (IC50 < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replication.

A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.