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Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.

G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.

The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.