James L. Stanton

Bio: James L. Stanton is an academic researcher from Novartis. The author has contributed to research in topics: Angiotensin-converting enzyme & Bicyclic molecule. The author has an hindex of 21, co-authored 52 publications receiving 1391 citations.

Amide derivatives and their use as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1

Abstract: Compounds of the formula (I) provide pharmacological agents which lower intracellular glucocorticoid concentrations in mammals, in particular, intracellular cortisol levels in humans. Therefore, the compounds of the instant invention improve insulin sensitivity in the muscle and the adipose tissue, and reduce lipolysis and free fatty acid production in the adipose tissue. The compounds of the invention lower hepatic glucocorticoid concentration in mammals, in particular, hepatic cortisol concentration in humans, resulting in inhibition of hepatic gluconeogenesis and lowering of plasma glucose levels. Thus, the compounds of the instant invention may be particularly useful in mammals as hypoglycemic agents for the treatment and prevention of conditions in which hyperglycemia and/or insulin resistance are implicated, such as type-2 diabetes. The compounds of the invention may also be used to treat other glucocorticoid associated disorders, such as Syndrome-X, dyslipidemia, hypertension and central obesity. The invention furthermore relates to the use of the compounds according to the invention for the preparation of medicaments, in particular of medicaments useful for the treatment and prevention of glucocorticoid associated disorders, by improving insulin sensitivity, reducing plasma glucose levels, reducing lipolysis and free fatty acid production, and by decreasing visceral adipose tissue formation.

Synthesis and biological properties of (carboxyalkyl)amino-substituted bicyclic lactam inhibitors of angiotensin converting enzyme.

Abstract: Syntheses of the potent angiotensin converting enzyme inhibitor (3S)-1-(carboxymethyl)-3-[[(1S)-1-carboxy-3-phenylpropyl]amino]- 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (4b; CGS 14831) and the related monoester prodrug (17a; CGS 14824A) are described together with preparative details for six- and eight-membered ring analogues. Inhibitory potencies and in vivo biological activity of the compounds are discussed. The data indicate that 17a has a biological profile comparable to that of enalapril.

Synthesis and structure-activity relationships of oxamic acid and acetic acid derivatives related to L-thyronine.

Abstract: Aryloxamic acids 7 and 23, (arylamino)acetic acids 29, arylpropionic acids 33, arylthioacetic acids 37, and (aryloxy)acetic acid 41 related to L-triiodothyronine (L-T3) were prepared and tested in vitro for binding to the rat liver nuclear L-T3 receptor and the rat membrane L-T3 receptor. The structure-activity relationships for these compounds are described, with 7f, 23a, 29c, 33a, 37b, and 41 showing excellent potency (IC50's of 0.19, 0.16, 1.1, 0.11, 3.5, and 0.10 nM, respectively) to the nuclear receptor and significantly lower binding affinity to the membrane receptor (IC50's > 5 microM). Some of these compounds, especially in the oxamic acid series 7 and 23, showed an unprecedented potency for methyl-substituted derivatives such as 7f and 23a. Compounds 7f and 23a showed good lipid lowering effects in rats with ED50's of 20 and 5 micrograms/kg po, respectively, and a lack of cardiac side effects in rats at doses as high as 10 and 25 mg/kg po, respectively.

Synthesis and biological activity of some transition-state inhibitors of human renin.

Abstract: A series of renin inhibitors containing the dipeptide transition state mimics (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyloctanoic acid (Leu (OH)/Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (CHa /(OH)/Val) was prepared. A structure-activity study with Boc-Phe-His-Leu (OH)/Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha (OH)/ Val- NHC4H9-n (8i) which has the length of a tetrapeptide and contains only one natural amino acid. Compound 8i had an IC50 of 2 x 10(-9) M against human renin and showed high enzyme specificity; IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 x 10(-6) and 3 x 10(-6) M, respectively). In salt-depleted marmosets, 8i inhibited plasma renin activity PRA and lowered blood pressure for up to 2 h after oral administration of a dose of 10 mg/kg.

Secondary Amides of (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic Acid as Inhibitors of Pyruvate Dehydrogenase Kinase

Abstract: N‘-Methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC50 = 180 μM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S,R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibi...

Multicomponent Reactions with Isocyanides.

Abstract: Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the “language” of MCRs, something that this review wishes to stimulate.

Inhibitors of farnesyl protein transferase

Abstract: The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras

Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates.

Abstract: Department of Chemistry, Tianjin University, Tianjin 300072, China; Department of Applied Chemistry, China Agricultural University, Beijing 100193, China; UMR 6014 CNRS, Laboratoire COBRA de l’IRCOF, Université et INSA de Rouen, Rue Tesniere, F-76130 Mont Saint Aignan, France; and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China