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1.
J Endocrinol ; 229(2): 85-96, 2016 05.
Article in English | MEDLINE | ID: mdl-26906745

ABSTRACT

Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity, but are ineffective after peripheral application, owing to a limited ability to cross the blood-brain barrier. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both Prrp-knockout and Prrp receptor-knockout mice. The aim of this study was to characterize the subchronic effect of a palmitoylated PrRP analog in two rat models of obesity and diabetes: diet-induced obese Sprague-Dawley rats and leptin receptor-deficient Zucker diabetic (ZDF) rats. In the rats with diet-induced obesity (DIO), a two-week intraperitoneal treatment with palmitoylated PrRP lowered food intake by 24% and body weight by 8%. This treatment also improved glucose tolerance and tended to decrease leptin levels and adipose tissue masses in a dose-dependent manner. In contrast, in ZDF rats, the same treatment with palmitoylated PrRP lowered food intake but did not significantly affect body weight or glucose tolerance, probably in consequence of severe leptin resistance due to a nonfunctional leptin receptor. Our data indicate a good efficacy of lipidized PrRP in DIO rats. Thus, the strong anorexigenic, body weight-reducing, and glucose tolerance-improving effects make palmitoylated PrRP an attractive candidate for anti-obesity treatment.


Subject(s)
Body Weight/drug effects , Obesity/drug therapy , Prolactin-Releasing Hormone/analogs & derivatives , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Appetite Depressants/pharmacology , Diabetes Mellitus, Experimental/metabolism , Diet, High-Fat/adverse effects , Drug Design , Eating/drug effects , Glucose Tolerance Test , Lipid Metabolism/drug effects , Lipid Metabolism/genetics , Lipoylation , Liver/drug effects , Liver/metabolism , Male , Mice , Obesity/metabolism , Obesity/pathology , Prolactin-Releasing Hormone/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Rats, Zucker , Receptors, Leptin/deficiency
2.
Eur J Med Chem ; 44(1): 332-44, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18406012

ABSTRACT

A series of arylalkanoic acid derivatives bearing methyl(phenethyl)amino groups were prepared and their inhibition of LTB(4) biosynthesis was evaluated. Regression analysis showed the slightly different parabolic dependences of this activity on lipophilicity of alpha-methyl and alpha-unsubstituted alkanoic acid derivatives. The relationship derived for alpha-unsubstituted alkanoic acids was extended by previously prepared group of similar derivatives of arylacetic acids without any change of regression coefficients and statistical criteria. It was concluded that the most active compounds belong to 2-arylpropanoic acid derivatives with lipophilicity close to logP(opt) (=6.97). But generally, the structural changes in the acidic part of compounds under study did not yield the substantial improvement of LTB(4) biosynthesis inhibition in comparison with the previously prepared series of derivatives IV. The anti-inflammatory effect of the compounds under study was evaluated in three animal models of inflammation and their possible utilization in the treatment of ulcerative colitis (UC) was followed. From 12 evaluated compounds, 4 compounds are more active in UC inhibition than the standard sulfasalazine but it can be stated that the change of connecting chain between aromatic ring and carboxyl did not bring about the important improvement of this activity in comparison with previous derivatives of arylacetic acids. Possible relation between LTB(4) biosynthesis inhibition and ulcerative colitis is seriously broken by the compound 8a with carbonyl as the additional functional group on the connecting chain between carboxyl and aromatic ring.


Subject(s)
Colitis, Ulcerative/drug therapy , Hydrocarbons, Aromatic/chemical synthesis , Receptors, Leukotriene B4/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Carboxylic Acids , Cells, Cultured , Gastrointestinal Agents/chemical synthesis , Gastrointestinal Agents/pharmacology , Hydrocarbons, Aromatic/pharmacology , Inflammation/drug therapy , Leukocytes , Quantitative Structure-Activity Relationship , Rats , Structure-Activity Relationship
3.
Eur J Med Chem ; 42(8): 1084-94, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17448575

ABSTRACT

A series of arylacetic acid derivatives bearing methyl(arylethyl)amino groups were prepared and their antileukotrienic activities involving LTB(4) were evaluated. Regression analysis has shown a strong dependence of these activities on lipophilicity for both LTB(4) receptor binding and inhibition of LTB(4) biosynthesis; parabolic relationships were derived. The values of slopes of the ascending linear parts of these dependences indicate various types of hydrophobic binding at the site of ligand interaction with relevant biomacromolecules. The anti-inflammatory effect of the compounds under study was also evaluated in three animal models of inflammation and their possible utilization in the treatment of ulcerative colitis (UC) was followed. The importance of antileukotrienic activities for the anti-inflammatory effect, especially in the model of UC was discussed, but further experiments are necessary to confirm the respective relations.


Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Colitis, Ulcerative/drug therapy , Leukotriene B4/antagonists & inhibitors , Acetamides/therapeutic use , Animals , Disease Models, Animal , Edema/chemically induced , Edema/drug therapy , Hydrophobic and Hydrophilic Interactions , Leukotriene B4/biosynthesis , Neutrophils/drug effects , Neutrophils/metabolism , Rats , Receptors, Leukotriene B4/antagonists & inhibitors , Receptors, Leukotriene B4/metabolism , Structure-Activity Relationship
4.
J Med Chem ; 50(7): 1495-503, 2007 Apr 05.
Article in English | MEDLINE | ID: mdl-17343371

ABSTRACT

The aim was to identify a novel selective PPARdelta agonist with full efficacy on free fatty acid (FFA) oxidation in vitro and plasma lipid correction in vivo. Using the triple PPARalpha,gamma,delta agonist 1 as the structural starting point, we wanted to investigate the possibility of obtaining selective PPARdelta agonists by modifying only the acidic part of 1, while holding the lipophilic half of the molecule constant. The structure-activity relationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidation efficacy performed in the rat muscle L6 cell line, and in vivo rat pharmacokinetic properties. Compound 7 ([4-[3,3-bis-(4-bromo-phenyl)-allylthio]-2-chloro-phenoxy]-acetic acid) was identified as a selective, partial agonist with good oral pharmacokinetic properties in rat. Chronic treatment of high fat fed ApoB100/CETP-Tgn mice with 7 corrected the plasma lipid parameters and improved insulin sensitivity. These data suggest that selective PPARdelta agonists have the potential to become a novel treatment of dyslipidemia.


Subject(s)
Allyl Compounds/chemical synthesis , Lipid Metabolism/drug effects , PPAR delta/agonists , Phenylacetates/chemical synthesis , Administration, Oral , Allyl Compounds/pharmacokinetics , Allyl Compounds/pharmacology , Animals , Apolipoprotein B-100/genetics , Binding Sites , Cell Line , Cholesterol Ester Transfer Proteins/genetics , Crystallography, X-Ray , Dietary Fats/administration & dosage , Fatty Acids, Nonesterified/metabolism , Female , Humans , Male , Mice , Mice, Transgenic , Models, Molecular , Muscle, Skeletal/cytology , Oxidation-Reduction , Phenylacetates/pharmacokinetics , Phenylacetates/pharmacology , Rats , Structure-Activity Relationship , Transcriptional Activation
5.
Arzneimittelforschung ; 55(8): 466-72, 2005.
Article in English | MEDLINE | ID: mdl-16149715

ABSTRACT

4-(2',4'- Difluorobiphenyl-4-yl)-2-methylbutyric acid (deoxoflobufen, VUFB 19053, CAS 847475-35-8) has been developed as a new omega-biphenyl-alkanoic acid and studied in comparison with the racemic form of 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (flobufen, CAS 112344-52-2). The compounds were tested in a series of models including acute inflammation induced by carrageenan, adjuvant arthritis, in vitro inhibition of the leuktotriene B4 (LTB4) production, reaction of the graft versus the host (GVHR), production of specific antibodies against ovalbumin, peritoneal exudate formation induced by thioglycollate and phagocytosis of thioglycollate-stimulated mouse peritoneal macrophages. Deoxoflobufen exhibited strong anti-inflammatory, antiarthritic and immunomodulatory effects in most of the performed tests. Anti-inflammatory and antiarthritic effects are fully comparable with those of flobufen, however, the compound is less toxic and has apparently stronger immunomodulating effects.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Biphenyl Compounds/pharmacology , Butyrates/pharmacology , Animals , Antibody Formation/drug effects , Area Under Curve , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Biphenyl Compounds/toxicity , Butyrates/toxicity , Carrageenan , Cell Adhesion/drug effects , Exudates and Transudates/drug effects , Female , Graft vs Host Disease/drug therapy , Hypersensitivity, Delayed/drug therapy , Inflammation/chemically induced , Inflammation/drug therapy , Leukotriene B4/biosynthesis , Macrophages/drug effects , Mice , Ovalbumin/immunology , Peritonitis/chemically induced , Peritonitis/drug therapy , Phagocytosis/drug effects , Pleurisy/chemically induced , Pleurisy/drug therapy , Rats , Structure-Activity Relationship , Thioglycolates
6.
J Med Chem ; 45(4): 789-804, 2002 Feb 14.
Article in English | MEDLINE | ID: mdl-11831892

ABSTRACT

Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC(50) = 0.36 microM) and PPARgamma (EC(50) = 0.17 microM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.


Subject(s)
Carbazoles/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Nuclear Proteins/agonists , Phenylpropionates/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Thiazolidinediones , Transcription Factors/agonists , Animals , Blood Glucose/metabolism , Carbazoles/chemistry , Carbazoles/pharmacokinetics , Carbazoles/pharmacology , Cholesterol/blood , Cholesterol, Dietary/administration & dosage , Crystallography, X-Ray , Drug Evaluation, Preclinical , Glucose Tolerance Test , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Male , Mice , Models, Molecular , Phenylpropionates/chemistry , Phenylpropionates/pharmacokinetics , Phenylpropionates/pharmacology , Pioglitazone , Rats , Rats, Sprague-Dawley , Rosiglitazone , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Triglycerides/blood
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