Design, Synthesis and SAR of Novel Analogues as Potent TRPV1 Antagonists and HIF-1α Inhibitors

Abstract

Abstract

Part 1. Urea Analogues with Benzooxazinone and Quinolinone as Potent TRPV1 Antagonists

A series of N-methylated and N-ethylhydroxylated 6,6 fused heterocycles were designed combining previously identified pharmacophoric elements (BCTC, M4 etc.) and evaluated as TRPV1 antagonists. This alkylation method was performed due to the desire of better antagonism and solubility. As a result of the FLIPR assay, the structure-activity relationship (SAR) analysis indicated that specific binding interactions of the 2-amino substituents in the C-region and the function of the secondary nitrogen on the A-region of the ligand were critical for high potency. Although the compounds activity dropped compared to the lead compounds, there were still some promising results. In particular, compound 111, 166, 193 were excellent TRPV1 antagonist (IC50 [CAP] near or below 1.0) and was thus approximately 2- to 5-fold more potent, respectively, than the parent compound BCTC (IC50 [CAP] = 2.5) for capsaicin antagonism. For further research, rat neuropathic model study and docking analysis is needed.

Part 2. Simple Amide Analogues from Deguelin as Potent HIF-1α Inhibitors

A series of analogues having a pyridine ring on its A-region and an amide linker on its B-region were synthesized as ring-truncated Deguelin surrogates and evaluated for their HIF-1α inhibition. Their structure-activity relationship was systematically investigated based on the variation of the linker B-region moiety. The potency of the compounds was checked by western blot assay. Among the inhibitors, compound 22 and 44 exhibited potent HIF-1α inhibition (HIF WB around 30) in a dose-dependent manner (approximately 2-fold more potent) and significant antitumor activity compared to Deguelin. To foster with these promising results, we need further docking study and characterized assays for cell viability, proliferation and migration.