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1.
Org Lett ; 21(5): 1268-1272, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30785295

ABSTRACT

An operationally simple oxidation-cyanation method for the synthesis of cyanamides is described. The procedure utilizes inexpensive and commercially available N-chlorosuccinimide and Zn(CN)2 as reagents to avoid direct handling of toxic cyanogen halides. It is demonstrated to be amenable for the cyanation of a variety of primary and secondary amines and aniline derivatives as well as a complex synthetic intermediate en route to verubecestat (MK-8931). Additionally, kinetic measurements and other control experiments are reported to shed light onto the mechanism of this cyanation reaction.

2.
Expert Opin Ther Pat ; 23(4): 531-6, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23409864

ABSTRACT

The patent application WO2012082947 claims novel compounds as agonists of a plasma membrane-bound bile acid receptor TGR5. By activating TGR5, the agonists improve glycemic control and enhance energy expenditure. The basic generic claim of the patent covers pyrazole derivatives, different permutations on the core pyrazole ring are covered in the subsidiary claims. The claimed compounds are human TGR5 agonists having potency in the nM range.


Subject(s)
Diabetes Mellitus/drug therapy , Hypoglycemic Agents/pharmacology , Pyrazoles/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Diabetes Mellitus/metabolism , Drug and Narcotic Control , Energy Metabolism/drug effects , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Molecular Structure , Patents as Topic , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Receptors, G-Protein-Coupled/metabolism , Structure-Activity Relationship
3.
Article in English | MEDLINE | ID: mdl-22216777

ABSTRACT

Last decade had witnessed enormous efforts to develop therapies to treat one or more components of metabolic syndrome, a cluster of diseases including diabetes, obesity and dyslipidemia. Several newer targets are identified and evaluated to treat these metabolic disorders. Microsomal triglyceride transfer protein (MTP) has been identified as one of the promising target for the treatment of dyslipidemia. MTP plays crucial role in the assembly of triglyceride rich chylomicrones in enterocytes and VLDL in hepatocytes and several lines of evidence suggested that MTP inhibitors can be instrumental in combating familial hypercholesterolemia. Several first generation compounds are currently being evaluated in clinic and fatty liver is found to be the main adverse effect of these agents. Recently development of enterocyte specific inhibitor of MTP is emphasized in order to deal with fatty liver issue. In this review, we have dealt with important mechanistic aspects of MTP inhibition, patent scenario and clinical trial outcomes and some of the recent patents related to newly discover chemical scaffolds.


Subject(s)
Carrier Proteins/antagonists & inhibitors , Dyslipidemias/drug therapy , Hypolipidemic Agents/therapeutic use , Animals , Carrier Proteins/metabolism , Dyslipidemias/metabolism , Fatty Liver/chemically induced , Humans , Hypolipidemic Agents/adverse effects , Lipid Metabolism/drug effects , Treatment Outcome
4.
Bioorg Med Chem Lett ; 21(10): 3103-9, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21450468

ABSTRACT

In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, novel thiophene substituted oxazole containing α-alkoxy-phenylpropanoic acid derivatives are designed as highly potent PPARα/γ dual agonists. These compounds were found to be efficacious at picomolar concentrations. Lead compound 18d has emerged as very potent PPARα/γ dual agonist demonstrating potent antidiabetic and lipid lowering activity at a very low dose and did not exhibit any significant signs of toxicity in rodents.


Subject(s)
PPAR alpha/agonists , PPAR gamma/agonists , Phenylpropionates/chemical synthesis , Phenylpropionates/pharmacology , Administration, Oral , Animals , Cell Line , Dose-Response Relationship, Drug , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Inhibitory Concentration 50 , Mice , Molecular Structure , Oxazoles/chemistry , Phenylpropionates/chemistry , Protein Binding/drug effects , Rats , Rats, Wistar , Rosiglitazone , Thiazolidinediones/chemical synthesis , Thiazolidinediones/chemistry , Thiazolidinediones/pharmacology , Thiophenes/chemistry
5.
Clin Exp Pharmacol Physiol ; 38(5): 338-44, 2011 May.
Article in English | MEDLINE | ID: mdl-21401695

ABSTRACT

1. Insulin-resistant states are commonly associated with a significantly higher risk of atherosclerosis. Insulin resistance has also been correlated with enhanced very low-density lipoprotein (VLDL) production, which is exacerbated by increased intestinal lipid synthesis and insulin-stimulated de novo lipogenesis. Microsomal triglyceride transfer protein (MTP) catalyses the critical step in the synthesis and secretion of VLDL and chylomicrons. The purpose of the present study was to test the hypothesis that chronic inhibition of MTP with a small molecule inhibitor would improve insulin sensitivity and reduce atherogenic risk in a genetic model of diabetic dyslipidaemia. 2. The in vivo activity of BMS-201038, a potent inhibitor of MTP, was evaluated in a model of hypertriglyceridemia induced by Triton WR1339 and corn oil in Zucker fatty rats. Triglyceride secretion rate was significantly reduced by a single dose of BMS-201038 by 35% at 0.3 mg/kg and 47% at 1 mg/kg, respectively. 3. Another group of Zucker fatty rats was dosed orally with BMS-201038 (0.3 and 1 mg/kg) for 14 days. Serum levels of triglycerides were reduced by 71% and 87%, non-esterified free fatty acids were reduced by 33% and 40%, and low-density lipoproteins by 26% and 29%, by 0.3 mg/kg and 1 mg/kg dose of BMS-201038, respectively. These serum lipid changes were accompanied by significant improvements in glucose tolerance and insulin sensitivity. In addition, lipid peroxidation in liver was reduced by 59% and 61%, and superoxide dismutase activity was increased by 11% and 45% by 0.3 mg/kg and 1 mg/kg dose of BMS-201038, respectively. Similar beneficial changes were found in aorta as well. 4. The present study provides evidence that inhibition of MTP with a small molecule inhibitor significantly improves dyslipidaemia associated with insulin resistance and reduces the atherosclerotic risk.


Subject(s)
Atherosclerosis/etiology , Atherosclerosis/prevention & control , Benzimidazoles/pharmacology , Carrier Proteins/antagonists & inhibitors , Insulin Resistance , Obesity/complications , Animals , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/pharmacology , Atherosclerosis/complications , Benzimidazoles/administration & dosage , Blood Glucose/drug effects , Blood Glucose/metabolism , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Drug Evaluation, Preclinical , Insulin Resistance/physiology , Lipid Metabolism/drug effects , Male , Metabolism/drug effects , Obesity/drug therapy , Rats , Rats, Zucker , Risk Factors
6.
Expert Opin Ther Pat ; 20(4): 593-6, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20192904

ABSTRACT

The patent application WO2008106213 describes the beneficial effects of thyroid hormone analogue 3,5 diiodothyropropionic acid (DITPA) such as stimulating weight loss in overweight mammals, lowering of triglyceride and treating metabolic syndrome in humans. The human population of the patients selected in the studies mentioned has a body mass index > 25. Two examples of the human clinical studies employing DITPA have been mentioned, namely, the body weight reduction and improvement in metabolic abnormalities in obese adults.


Subject(s)
Diiodothyronines/pharmacology , Obesity/drug therapy , Propionates/pharmacology , Thyroid Hormones/pharmacology , Adult , Animals , Clinical Trials as Topic , Humans , Metabolic Syndrome/drug therapy , Overweight/drug therapy , Patents as Topic , Triglycerides/metabolism , Weight Loss/drug effects
7.
Bioorg Med Chem Lett ; 18(14): 3919-24, 2008 Jul 15.
Article in English | MEDLINE | ID: mdl-18585912

ABSTRACT

Design and synthesis of a novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives are reported and their in vitro thyroid hormone receptor selectivity has been evaluated in the thyroid luciferase receptor assay. The 3-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenylamino]-4-hydroxy-cyclobut-3-ene-1,2-dione 21 has shown selectivity towards thyroid hormone receptor beta.


Subject(s)
Cyclobutanes/chemistry , Thyroid Hormone Receptors beta/chemistry , Thyroid Hormone Receptors beta/metabolism , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray , Drug Design , Humans , Ligands , Luciferases/metabolism , Models, Chemical , Molecular Conformation , Phenyl Ethers/pharmacology , Phenylacetates/pharmacology , Protein Binding , Structure-Activity Relationship , Thyroid Gland/enzymology , Thyroid Hormone Receptors alpha/metabolism
8.
J Med Chem ; 50(24): 5951-66, 2007 Nov 29.
Article in English | MEDLINE | ID: mdl-17979261

ABSTRACT

A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compounds--the bisulfate salt of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30--showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.


Subject(s)
Amides/chemical synthesis , Anti-Obesity Agents/chemical synthesis , Pyrazoles/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Appetite Depressants/chemical synthesis , Appetite Depressants/pharmacokinetics , Appetite Depressants/pharmacology , Body Weight/drug effects , Female , Models, Molecular , Morpholines/chemical synthesis , Morpholines/pharmacokinetics , Morpholines/pharmacology , Piperidines/chemistry , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Zucker , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Rimonabant , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry
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