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1.
ACS Med Chem Lett ; 13(8): 1248-1254, 2022 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-35978682

RESUMEN

Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist 12 (MK-1462), which was advanced into clinical trials.

2.
Bioorg Med Chem Lett ; 28(23-24): 3721-3725, 2018 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-30348490

RESUMEN

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.


Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Lipasa/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacología , Animales , HDL-Colesterol/sangre , HDL-Colesterol/metabolismo , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/síntesis química , Humanos , Lipasa/sangre , Lipasa/metabolismo , Ratones , Modelos Moleculares , Pirimidinonas/sangre , Pirimidinonas/síntesis química , Relación Estructura-Actividad
3.
J Med Chem ; 60(23): 9703-9723, 2017 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-29077405

RESUMEN

Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.


Asunto(s)
Anticoagulantes/química , Anticoagulantes/uso terapéutico , Factor XIa/antagonistas & inhibidores , Isoquinolinas/química , Isoquinolinas/uso terapéutico , Trombosis/tratamiento farmacológico , para-Aminobenzoatos/química , para-Aminobenzoatos/uso terapéutico , Animales , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Coagulación Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Perros , Descubrimiento de Drogas , Factor XIa/química , Factor XIa/metabolismo , Humanos , Isoquinolinas/farmacocinética , Isoquinolinas/farmacología , Masculino , Simulación del Acoplamiento Molecular , Conejos , Ratas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Trombosis/sangre , para-Aminobenzoatos/farmacocinética , para-Aminobenzoatos/farmacología
4.
Antimicrob Agents Chemother ; 60(8): 4830-9, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27246784

RESUMEN

Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo.


Asunto(s)
Antibacterianos/farmacología , Ciclooctanos/farmacología , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , ADN-Topoisomerasas de Tipo II/metabolismo , Inhibidores de Topoisomerasa II/farmacología , Animales , Línea Celular , ADN Bacteriano/genética , Perros , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Infecciones por Escherichia coli/tratamiento farmacológico , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Ratas , Ratas Wistar , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética
5.
AAPS J ; 17(1): 144-55, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25398427

RESUMEN

Peptides are an important class of endogenous ligands that regulate key biological cascades. As such, peptides represent a promising therapeutic class with the potential to alleviate many severe disease states. Despite their therapeutic potential, peptides frequently pose drug delivery challenges to scientists. This review introduces the physicochemical, biophysical, biopharmaceutical, and formulation developability aspects of peptides pertinent to the drug discovery-to-development interface. It introduces the relevance of these properties with respect to the delivery modalities available for peptide pharmaceuticals, with the parenteral route being the most prevalent route of administration. This review also presents characterization strategies for oral delivery of peptides with the aim of illuminating developability issues with the drug candidate. A brief overview of other routes of administration, including inhaled, transdermal, and intranasal routes, is provided as these routes are generally preferred by patients over injectables. Finally, this review presents formulation techniques to mitigate some of the developability obstacles associated with peptide delivery. The authors emphasize opportunities for the thoughtful application of pharmaceutical science to the development of peptide drugs and to the general advancement of this promising class of pharmaceuticals.


Asunto(s)
Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Péptidos/administración & dosificación , Química Farmacéutica/métodos , Vías de Administración de Medicamentos , Humanos , Prioridad del Paciente
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