ABSTRACT
The synthesis of substituted phenoxyphenyl oxamic acid derivatives related to L-thyronine (L-T3) is described. The in vitro and in vivo cholesterol lowering and cardiovascular effects of these compounds are presented and discussed.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacology , Cardiovascular Agents/chemical synthesis , Cardiovascular Agents/pharmacology , Oxamic Acid/analogs & derivatives , Thyronines/chemistry , Animals , Anticholesteremic Agents/chemistry , Cardiovascular Agents/chemistry , In Vitro Techniques , Oxamic Acid/chemical synthesis , Oxamic Acid/chemistry , Oxamic Acid/pharmacology , RatsABSTRACT
N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) 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 (>1,000-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) inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.
Subject(s)
Enzyme Inhibitors/pharmacology , Propionates/pharmacology , Protein Kinase Inhibitors , Protein Kinases , Amides , Animals , Area Under Curve , Biological Availability , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Lactic Acid/blood , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred C57BL , Propionates/chemistry , Propionates/pharmacokinetics , Protein Serine-Threonine Kinases , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Rats , Rats, Sprague-DawleyABSTRACT
The preparation of a series of 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid derivatives 5a-y by reductive amination of 2,3,4,5-tetrahydro-1H-1-benzazepine-2,3-dione (7) with L-amino acid derivatives is described. The compounds were tested for inhibition of angiotensin converting enzyme. The structure-activity profile of the series is discussed. Compound 5a was especially potent when tested in dogs for inhibition of angiotensin I pressor response, having an ID50 = 0.07 mg/kg po.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Benzazepines/pharmacology , Amino Acids , Animals , Benzazepines/chemical synthesis , Benzazepines/therapeutic use , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Dogs , Hypertension/drug therapy , Rats , Rats, Inbred SHR , Structure-Activity RelationshipABSTRACT
The synthesis, analgetic activity, and physical dependence capacity of a large number of 5-phenyl-6,7-benzomorphan derivatives are described. Observations made during the Stevens' rearrangement of 1-benzyl-1-methyl-delta 3-piperidinium salt derivatives (V) under various conditions are discussed. The absolute configuration of the 9-demethyl series and the 2'-deoxy series is established by comparison of their ORD and CD spectra with those of 49, whose absolute configuration was previously established by X-ray crystallography. A convenient synthesis of 3H-labeled phenols using 3H3PO4 is described, as well as the preparation of 14C-labeled compounds by conventional methods.
