David L. Musso

Synthesis and evaluation of the anticonvulsant activity of a series of 2-amino-1-phenyl-1-propanols derived from the metabolites of the antidepressant bupropion

Abstract A series of 2-amino-1-phenyl-1-propanols that are structurally related to known metabolites of bupropion,1 (Wellbutrin®) were synthesized and evaluated as potential anticonvulsants. The ( R ∗ ,R ∗ )-2-tert- butylamino -1-(3- trifluoromethylphenyl ) propanol 20 had an ED50 of 16.5 ± 2.8 mg/kg ip in mice in the maximal electroshock screen and was chosen for further evaluation.

N-hydroxyformamide peptidomimetics as TACE/matrix metalloprotease inhibitors: oral activity via P1' isobutyl substitution.

N-Hydroxyformamide-class metalloprotease inhibitors were designed and synthesized, which have potent broad-spectrum activity versus matrix metalloproteases and TNF-alpha converting enzyme (TACE). Compound 13c possesses good oral and intravenous pharmacokinetics in the rat and dog.

Discovery of small molecule agonists for the bombesin receptor subtype 3 (BRS-3) based on an omeprazole lead.

Starting from a weak omeprazole screening hit, replacement of the pyridine with a 1,3-benzodioxole moiety, modification of the thioether linkage, and substitution of the benzimidazole pharmacophore led to the discovery of nanomolar BRS-3 agonists.

Novel 3-phenylprop-2-ynylamines as inhibitors of mammalian squalene epoxidase

The synthesis of a novel series of 3-phenylprop-2-ynylamines as selective mammalian squalene epoxidase inhibitors is described. Structure activity relationship studies led to the discovery of compound 19, 1-[3-(3,5-dichlorophenyl)-prop-2-ynyl]-3- methylpiperidine hydrochloride with an IC50 of 2.8 +/- 0.6 microM against rat liver squalene epoxidase. Against 23 strains of fungal squalene epoxidase compound 19 was found to be inactive.

Improved Synthesis of 5-Benzyl-2-thiouracils

Abstract Improved methodology for the synthesis of 5-benzyl-2-thiouracils from ethyl phenylpropanoates is reported.

Design and synthesis of a chiral hapten for a radioimmunoassay of the antidepressant (2S, 3S, 5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol hydrochloride

Abstract The synthesis of a hapten for a radioimmunoassay of the antidepressant (2S, 3S, 5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol hydrochloride is described.

Separations of Threo-Erythro Aminoalcohols by Preparative HPLC

Abstract A liquid chromatographic method which enables the separation of the threo/erythro diastereoisomers obtained from the reduction of WellbutrinTM brand bupropion using a ternary eluent system is described. This has been achieved on a preparative scale.

N-substituted phenylbenzamides of the niclosamide chemotype attenuate obesity related changes in high fat diet fed mice

Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is generally exhibited by non-progressive simple steatosis. However, a significant subset of patient’s progress to nonalcoholic steatohepatitis (NASH) that is defined by the presence of steatosis, inflammation and hepatocyte injury with fibrosis. Unfortunately, there are no approved therapies for NAFLD or NASH and therefore therapeutic approaches are urgently needed. Niclosamide is an U.S. Food and Drug Administration (FDA)-approved anthelmintic drug that mediates its effect by uncoupling oxidative phosphorylation. Niclosamide and its salt forms, Niclosamide Ethanolamine (NEN), and Niclosamide Piperazine (NPP) have shown efficacy in murine models of diet induced obesity characterized by attenuation of the prominent fatty liver disease phenotype and improved glucose metabolism. While the exact mechanism(s) underlying these changes remains unclear, the ability to uncouple oxidative phosphorylation leading to increased energy expenditure and lipid metabolism or attenuation of PKA mediated glucagon signaling in the liver have been proposed. Unfortunately, niclosamide has very poor water solubility, leading to low oral bioavailability. This, in addition to mitochondrial uncoupling activity and potential genotoxicity have reduced enthusiasm for its clinical use. More recently, salt forms of niclosamide, NEN and NPP, have demonstrated improved oral bioavailability while retaining activity. This suggests that development of safer more effective niclosamide derivatives for the treatment of NAFLD and Type 2 Diabetes may be possible. Herein we explored the ability of a series of N-substituted phenylbenzamide derivatives of the niclosamide salicylanilide chemotype to attenuate hepatic steatosis using a novel phenotypic in vitro model of fatty liver and the high fat diet-fed mouse model of diet induced obesity. These studies identified novel compounds with improved pre-clinical properties that attenuate hepatic steatosis in vitro and in vivo. These compounds with improved drug properties may be useful in alleviating symptoms and protection against disease progression in patients with metabolic syndrome and NAFLD.