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1.
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
2.
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
3.
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
4.
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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