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1.
J Med Chem ; 66(16): 11428-11446, 2023 08 24.
Article in English | MEDLINE | ID: mdl-37552807

ABSTRACT

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPARδ agonist available for clinical use. We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening methods. In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPARδ activity and subtype selectivity. This led to the discovery of 21 having strong PPARδ agonist activity (EC50 = 3.6 nM) with excellent ADME properties. Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.


Subject(s)
Atherosclerosis , PPAR delta , Mice , Animals , PPAR delta/agonists , Atherosclerosis/drug therapy , Anti-Inflammatory Agents , Thiazoles , Piperidines/pharmacology
2.
Bioorg Med Chem ; 82: 117215, 2023 03 15.
Article in English | MEDLINE | ID: mdl-36840990

ABSTRACT

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a target for treating metabolic syndrome, whereas there is no PPARδ agonist in clinical use. Previously, we have reported the discovery of 2-(1-piperidinyl)-1,3-benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening techniques. In this study, we performed the further optimization study of the lead compound 1 focusing on improvement of hydrophobic interactions in the binding site to enhance agonist efficacy for PPARδ and subtype selectivity, thereby discovering a novel PPARδ agonist 5g which exhibited high in vitro agonist activity (hPPARδ, EC50 = 4.1 nM) and sufficiently high selectivity ratio over PPARα and PPARγ. Moreover, 5g revealed a significant upregulation of high-density lipoprotein cholesterol level in vivo.


Subject(s)
Benzothiazoles , PPAR delta , Structure-Activity Relationship , Benzothiazoles/pharmacology , Binding Sites , Transcriptional Activation , PPAR delta/agonists
3.
Bioorg Med Chem Lett ; 59: 128567, 2022 03 01.
Article in English | MEDLINE | ID: mdl-35063634

ABSTRACT

Novel PPARδ agonists, 2-(1-piperidinyl)-1,3-benzothiazole derivatives were discovered by our proprietary docking-based virtual screening technique. Compound 1 as the initial hit was effectively modified to acquire PPARδ agonist activity, resulting in the discovery of compound 12 with high agonistic potency for PPARδ and selectivity over PPARα and PPARγ. Compound 12 also had good ADME profiles and showed in vivo efficacy as a lead.


Subject(s)
Benzothiazoles/pharmacology , Drug Discovery , PPAR delta/agonists , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Molecular Structure , PPAR alpha/agonists , PPAR gamma/agonists , Structure-Activity Relationship
4.
Phys Rev E ; 93(1): 010501, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26871011

ABSTRACT

A self-oscillating gel is a system that generates an autonomous volume oscillation. This oscillation is powered by the chemical energy of the Belousov-Zhabotinsky (BZ) reaction, which demonstrates metal ion redox oscillation. A self-oscillating gel is composed of Poly-N-isopropylacrylamide (PNIPAAm) with a metal ion. In this study, we found that the displacement of the volume oscillation in a self-oscillating gel could be controlled by its being subjected to a prestraining process. We also revealed the driving mechanism of the self-oscillating gel from the point of view of thermodynamics. We observed that the polymer-solvent interaction parameter χ is altered by the redox changes to the metal ion incorporated in the self-oscillating gel. The prestraining process leads to changes in χ and changes in enthalpy and entropy when the self-oscillating gel is in a reduced and oxidized state. We found that nonprestrained gel samples oscillate in a poor solution (χ>0.5) and prestrained gel samples oscillate in a good solution (χ<0.5).


Subject(s)
Acrylic Resins/chemistry , Gels/chemistry , Ions/chemistry , Metals/chemistry , Models, Chemical , Motion , Osmotic Pressure , Oxidation-Reduction , Periodicity , Solvents/chemistry , Thermodynamics , Water/chemistry
5.
Org Biomol Chem ; 1(14): 2468-73, 2003 Jul 21.
Article in English | MEDLINE | ID: mdl-12956063

ABSTRACT

Several beta-secretase inhibitors were designed based on hydroxyethylamine dipeptide isostere (HDI) structures and were synthesized by a methodology using the aza-Payne rearragement and O,N-acyl transfer reactions to study their structure-activity relationships. Among these pseudopeptides, effective compounds were developed as the first beta-secretase inhibitors containing the HDI transition state mimic with potent enzyme inhibitory activity (IC50 < 100 nM).


Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Dipeptides/chemistry , Ethylamines/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Acylation , Amino Acid Sequence , Aspartic Acid Endopeptidases/genetics , Aza Compounds/chemistry , Esterification , Humans , Inhibitory Concentration 50 , Isoenzymes , Molecular Mimicry , Oligopeptides/chemistry , Oligopeptides/pharmacology , Protease Inhibitors/chemical synthesis , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Structure-Activity Relationship
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