2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists.

A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure-activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.

Discovery of 1-(1H-indazol-4-yl)-3-((1-phenyl-1H-pyrazol-5-yl)methyl) ureas as potent and thermoneutral TRPV1 antagonists.

A series of 1-indazol-3-(1-phenylpyrazol-5-yl)methyl ureas were investigated as hTRPV1 antagonists. The structure-activity relationship study was conducted systematically for both the indazole A-region and the 3-trifluoromethyl/t-butyl pyrazole C-region to optimize the antagonism toward the activation by capsaicin. Among them, the antagonists 26, 50 and 51 displayed highly potent antagonism with Ki(CAP) = 0.4-0.5 nM. Further, in vivo studies in mice indicated that these derivatives both antagonized capsaicin induced hypothermia, consistent with their in vitro activity, and themselves did not induce hyperthermia. In the formalin model, 51 showed anti-nociceptive activity in a dose-dependent manner.

Functional Group-Dependent Induction of Astrocytogenesis and Neurogenesis by Flavone Derivatives.

Neural stem cells (NSCs) differentiate into multiple cell types, including neurons, astrocytes, and oligodendrocytes, and provide an excellent platform to screen drugs against neurodegenerative diseases. Flavonoids exert a wide range of biological functions on several cell types and affect the fate of NSCs. In the present study, we investigated whether the structure-activity relationships of flavone derivatives influence NSC differentiation. As previously reported, we observed that PD98059 (2'-amino-3'-methoxy-flavone), compound 2 (3'-methoxy-flavone) induced astrocytogenesis. In the present study, we showed that compound 3 (2'-hydroxy-3'-methoxy-flavone), containing a 3'-methoxy group, and a non-bulky group at C2' and C4', induced astrocytogenesis through JAK-STAT3 signaling pathway. However, compound 1 and 7-12 without the methoxy group did not show such effects. Interestingly, the compounds 4 (2',3'-dimethoxyflavone), 5 (2'-N-phenylacetamido-3'-methoxy-flavone), and 6 (3',4'-dimethoxyflavone) containing only 3'-methoxy could not promote astrocytic differentiation, suggesting that both the methoxy groups at C3' and non-bulky group at C2' and C4' are required for the induction of astrocytogenesis. Notably, compound 6 promoted neuronal differentiation, whereas its 4'-demethoxylated analog, compound 2, repressed neurogenesis, suggesting an essential role of the methoxy group at C4' in neurogenesis. These findings revealed that subtle structural changes of flavone derivatives have pronounced effects on NSC differentiation and can guide to design and develop novel flavone chemicals targeting NSCs fate regulation.

Discovery of an Orally Bioavailable Benzofuran Analogue That Serves as a ß-Amyloid Aggregation Inhibitor for the Potential Treatment of Alzheimer's Disease.

We developed an orally active and blood-brain-barrier-permeable benzofuran analogue (8, MDR-1339) with potent antiaggregation activity. Compound 8 restored cellular viability from Aß-induced cytotoxicity but also improved the learning and memory function of AD model mice by reducing the Aß aggregates in the brains. Given the high bioavailability and brain permeability demonstrated in our pharmacokinetic studies, 8 will provide a novel scaffold for an Aß-aggregation inhibitor that may offer an alternative treatment for AD.