Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were determined by X-ray crystallography, and the inhibitors were found to bind in an allosteric binding site separate from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compounds in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.

No abstract

The cytotoxicity of the 10mer ODN FdUMP[10] towards human colorectal tumor cells was evaluated using a clonogenic assay. FdUMP[10] was more than 100-fold more active than 5-FU at inhibiting colony formation of H630 cells. FdUMP[10] was also evaluated for cytotoxicity in the NCI 60 cell line screen, and showed markedly improved activity relative to 5-FU against numerous tumor cell lines. The in-vivo tolerance of FdUMP[10] is more than three-fold greater per mole fluorinated pyrimidine, than 5-FU.

No abstract

No abstract

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1. KEYWORDS: GPR40, full agonist, AM-1638, AMG 837, insulin secretagogue, FFA1 T ype II diabetics lose their ability to maintain glucose homeostasis due to defects in both insulin secretion and action.1 GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets.2 When activated by medium to long chain fatty acids, GPR40 elicits increased insulin secretion only in the presence of elevated glucose levels. 3This alluring mechanism to treat type II diabetes presents the potential of little or no risk of hypoglycemia and has been investigated by multiple groups, leading to the discovery of several clinical candidates.4−7 We previously described the discovery of AMG 837 (1), 8−10 a small molecule partial agonist of GPR40 that displays oral efficacy in a variety of rodent diabetic models without exhibiting hypoglycemia. Because of the robust antidiabetic activity and favorable pharmacokinetic properties, 1 was selected for clinical evaluation. Because the ability of partial agonist 1 to maintain glycemic control was being tested in a clinical setting, we became interested in interrogating GPR40 with full agonists. We hypothesized that a GPR40 full agonist should have a greater ability to induce insulin secretion and thus provide greater glycemic control. In this letter, we describe in detail the structure−activity relationship (SAR) studies that started from the GPR40 partial agonist 1 and culminate with the identification of GPR40 full agonist AM-1638 (21) and provide further evidence that GPR40 full agonists demonstrate superior efficacy over partial agonists when evaluated in vivo.To provide a greater dynamic range with which to assess improvements in intrinsic efficacy, we chose to reevaluate compounds previously synthesized toward discovery of partial agonist 1 in CHO cells transfected with lower levels of GPR40 expression plasmid [from 5.0 ( Figure 1A) to 0.05 μg ( Figure 1B)].9 Under the original 5.0 μg plasmid conditions, partial agonist 1 demonstrates 75% of the response (E max ) shown by the natural free fatty acid ligand docosahexaenoic acid (DHA) ( Figure 1A). In contrast, reducing the expression plasmid to 0.05 μg affords an assay with the appropriate dynamic range to distinguish GPR40 partial and full agonists. As depicted in Figure 1B, partial agonist 1 dis...

No abstract

No abstract