ABSTRACT
Tirzepatide, the first approved dual GLP-1/GIP receptor agonist (RA), has achieved better clinical outcomes than other GLP-1RAs. However, it is an imbalanced dual GIP/GLP-1 RA, and it remains unclear whether the degree of imbalance is optimal. Here, we present a novel long-acting dual GLP-1/GIP RA that exhibits better activity than tirzepatide toward GLP-1R. A candidate conjugate, D314, identified via peptide design, synthesis, conjugation, and experimentation, was evaluated using chronic studies in db/db and diet induced obese (DIO) mice. D314 achieved favorable blood glucose and body weight-lowering effects, equal to those of tirzepatide. Its half-life in dogs (T1/2: 78.3 ± 14.01 h) reveals its suitability for once-weekly administration in humans. This preclinical study suggests the potential role of D314 as an effective agent for treating T2DM and obesity.
Subject(s)
Diabetes Mellitus, Type 2 , Glucagon-Like Peptide 1 , Receptors, Gastrointestinal Hormone , Animals , Dogs , Humans , Mice , Blood Glucose , Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide 1/agonists , Glucagon-Like Peptide-1 Receptor/agonists , Hypoglycemic Agents/pharmacology , Obesity/drug therapy , Receptors, Gastrointestinal Hormone/agonists , Receptors, Gastrointestinal Hormone/therapeutic useABSTRACT
A method for separation and determination of 32 fentanyl-related substances, including seven sets of isomeric fentanyl analogues, was developed using ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap high-resolution mass spectrometry. The collision energy, chromatographic column, and mobile phase were optimized. All compounds were efficiently flushed out of a universal C18 column with a soft gradient consisting of solvent A (2 mM ammonium formate and 0.1% formic acid in water) and solvent B (2 mM ammonium formate and 0.1% formic acid in methanol) in only 20 min, achieving excellent resolution. Detection and analysis were carried out simultaneously in the positive ion mode using the full scan and data-dependent tandem mass spectrometry modes with a normalized collision energy of 40. The method was validated in terms of limit of detection, limit of quantification, linearity, accuracy, and precision. For all fentanyl-related substances, the limit of detection (0.5 ng/mL) and limit of quantification (1 ng/mL) were adequate for screening and quantification in daily drug control. Calibration curves for all compounds were established in the range of 1-500 ng/mL. The intra- and interday precision (RSD%) were within 0.4-2.3 and 0.7-2.7%, respectively. The accuracy ranged from 99 to 106%. The method was applied to analyze seized drug samples.
Subject(s)
Chromatography, High Pressure Liquid/methods , Fentanyl/analysis , Mass Spectrometry/methods , Calibration , Isomerism , Narcotics/analysisABSTRACT
A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes. As the results of structure-activity relationship (SAR) study of the series, the compounds with 4-methyl-quinazoline-2-yl-methyl group at N-1 position and 2-aminoethylaminomethyl group gave better activities. Compounds H4 and H9 showed good DPP-4 inhibition and more than 100-fold selectivity over DPP-7 and DPP-8.
Subject(s)
Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Xanthine/chemistry , Binding Sites , Catalytic Domain , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism , Humans , Molecular Docking Simulation , Structure-Activity Relationship , Xanthine/chemical synthesis , Xanthine/therapeutic useABSTRACT
A series of calcium (3R,5S,6E)-7-[4,6,7,8-substituted-quinoline-3-yl]-3,5-dihydroxy-hept-6-enoates was synthesized from the lactones, and the anti-hypercholesterolemic evaluation in quails was presented in this report. It was found that most of the compounds significantly decreased levels of total cholesterol and low-density lipoprotein. 2e showed better hypolipidemic effect than atorvastatin, and 2d and 2j exhibited comparable efficacy to atorvastatin. These three compounds were selected as the hypocholesterolemic candidates for further evaluation.
Subject(s)
Anticholesteremic Agents/chemistry , Anticholesteremic Agents/therapeutic use , Calcium/chemistry , Calcium/therapeutic use , Hypercholesterolemia/drug therapy , Mevalonic Acid/chemistry , Mevalonic Acid/pharmacology , Animals , Anticholesteremic Agents/chemical synthesis , Cholesterol/metabolism , Lipoproteins, LDL/metabolism , Male , Mevalonic Acid/chemical synthesis , Quail , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/therapeutic use , Salts/chemical synthesis , Salts/chemistry , Salts/therapeutic useABSTRACT
A series of novel 4-thiophenyl quinoline-based mevalonolactone derivatives were synthesized from ethyl 6,7,8-trisubstituted-4-chloro-quinoline-3-carboxylates by several reactions and evaluated for their ability to inhibit the rat HMG CoA reductase in vitro. It was found that substitution with a variety of thiophenyl groups at position 4 in quinoline resulted in retention or enhancement of the inhibition and the preferable groups were 4-isopropyl-thiophenyl and 3-methoxy-thiophenyl. (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-isopropylthiophenyl-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A16) and (4R, 6S)-6-[(E)-2-(6-fluoro-4,7-di-(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A23) were approximately three times more potent than rosuvastatin or pitavastatin in inhibiting HMG CoA reductase and selected as the hypocholesterolemic candidates for further evaluation.
