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1.
Nat Commun ; 9(1): 1645, 2018 04 25.
Article in English | MEDLINE | ID: mdl-29695780

ABSTRACT

Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), γ-linolenic acid, can be computationally modeled in this site. Both γ-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/pharmacology , Incretins/metabolism , Insulin Secretion , Receptors, G-Protein-Coupled/agonists , Allosteric Site/genetics , Animals , Benzofurans/pharmacology , Benzofurans/therapeutic use , Crystallography, X-Ray , Diabetes Mellitus, Type 2/metabolism , Drug Synergism , HEK293 Cells , Humans , Hypoglycemic Agents/therapeutic use , Insulin/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Knockout , Molecular Docking Simulation , Mutagenesis, Site-Directed , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sulfones/pharmacology , Sulfones/therapeutic use , gamma-Linolenic Acid/metabolism
2.
J Med Chem ; 59(12): 5904-10, 2016 06 23.
Article in English | MEDLINE | ID: mdl-27213958

ABSTRACT

To develop novel treatments for type 2 diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.


Subject(s)
Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Serine C-Palmitoyltransferase/antagonists & inhibitors , Administration, Oral , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Imidazoles/administration & dosage , Imidazoles/chemistry , MCF-7 Cells , Male , Mice , Mice, Obese , Molecular Structure , Piperidines/administration & dosage , Piperidines/chemistry , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyridines/administration & dosage , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Serine C-Palmitoyltransferase/metabolism , Structure-Activity Relationship
3.
J Med Chem ; 58(24): 9768-72, 2015 Dec 24.
Article in English | MEDLINE | ID: mdl-26568144

ABSTRACT

The farnesoid X receptor (FXR) is a member of the "metabolic" subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr-/- mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed.


Subject(s)
Dyslipidemias/drug therapy , Hypolipidemic Agents/chemistry , Indoles/chemistry , Isoxazoles/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Cholesterol/blood , Dogs , Double-Blind Method , Female , HEK293 Cells , Humans , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Indoles/pharmacokinetics , Indoles/pharmacology , Isoxazoles/pharmacokinetics , Isoxazoles/pharmacology , Macaca fascicularis , Male , Mice , Mice, Knockout , Rats , Rats, Sprague-Dawley , Receptors, LDL/genetics , Structure-Activity Relationship , Triglycerides/blood
4.
Bioorg Med Chem Lett ; 25(7): 1377-80, 2015 Apr 01.
Article in English | MEDLINE | ID: mdl-25752984

ABSTRACT

The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor ß (TRß) agonists is described. Compounds with >50× binding selectivity for TRß over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo.


Subject(s)
Acetates/pharmacology , Drug Design , Indoles/pharmacology , Thyroid Hormone Receptors beta/agonists , Acetates/chemical synthesis , Acetates/chemistry , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 17(12): 3349-53, 2007 Jun 15.
Article in English | MEDLINE | ID: mdl-17434304
6.
Bioorg Med Chem Lett ; 13(23): 4235-9, 2003 Dec 01.
Article in English | MEDLINE | ID: mdl-14623008

ABSTRACT

The oxazolidinones are promising agents for the treatment of infections caused by gram-positive bacteria, including multidrug-resistant strains. In ongoing studies we have discovered that a strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC's<0.5 microg/mL for the most potent congeners). The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of alpha-methylated indoline derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed.


Subject(s)
Anti-Bacterial Agents , Drug Design , Hydroquinones , Indoles , Oxazines , Oxazolidinones , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hydroquinones/chemical synthesis , Hydroquinones/pharmacokinetics , Hydroquinones/pharmacology , Indoles/chemical synthesis , Indoles/pharmacokinetics , Indoles/pharmacology , Microbial Sensitivity Tests , Oxazines/chemical synthesis , Oxazines/pharmacokinetics , Oxazines/pharmacology , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacokinetics , Oxazolidinones/pharmacology , Structure-Activity Relationship
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