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1.
Bioorg Med Chem Lett ; 30(16): 127072, 2020 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-32340773

RESUMEN

A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC50 = 1 nM and FXIa IC50 = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.


Asunto(s)
Anticoagulantes/farmacología , Diseño de Fármacos , Factor XIa/antagonistas & inhibidores , Prolina/farmacología , Anticoagulantes/síntesis química , Anticoagulantes/química , Relación Dosis-Respuesta a Droga , Factor XIa/metabolismo , Humanos , Estructura Molecular , Prolina/síntesis química , Prolina/química , Relación Estructura-Actividad
2.
Bioorg Med Chem ; 16(16): 7535-42, 2008 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-18691892

RESUMEN

A series of betamethasone 17alpha-carbamates were designed, synthesized, and evaluated for their ability to dissociate the two main functions of the glucocorticoid receptor, that is, transactivation and transrepression, in rat cell lines. A number of alkyl substituted betamethasone 17alpha-carbamates were identified with excellent affinity for the glucocorticoid receptor (e.g., 7, GR IC(50) 5.1 nM) and indicated dissociated profiles in functional assays of transactivation (rat tyrosine aminotransferase, TAT, and rat glutamine synthetase, GS) and transrepression (human A549 cells, MMP-1 assay). Gratifyingly, the in-vivo profile of these compounds, for example, 7, also indicated potent anti-inflammatory activity with impaired effects on glucose, insulin, triglycerides, and body weight. Taken together, these results indicate that dissociated glucocorticoid receptor modulators can be identified in rodents.


Asunto(s)
Betametasona/análogos & derivados , Carbamatos/síntesis química , Receptores de Glucocorticoides/metabolismo , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Betametasona/síntesis química , Betametasona/farmacocinética , Betametasona/farmacología , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Carbamatos/química , Carbamatos/farmacocinética , Carbamatos/farmacología , Glutamato-Amoníaco Ligasa/metabolismo , Insulina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Ratas , Receptores de Glucocorticoides/química , Triglicéridos/sangre , Tirosina Transaminasa/metabolismo
3.
Diabetes ; 67(6): 1173-1181, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29540491

RESUMEN

We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3-3H]glucose began at -120 min. Basal sampling (-30 to 0 min) was followed by two study periods (150 min each), clamp period 1 (P1) and clamp period 2 (P2). At 0 min, somatostatin and GRI (36 ± 3 pmol/kg/min) or HI (1.8 pmol/kg/min) were infused intravenously; basal glucagon was replaced intraportally. Glucose was infused intravenously to clamp plasma glucose at 80 mg/dL (P1) and 240 mg/dL (P2). Whole-body insulin clearance and insulin concentrations were not different in P1 versus P2 with HI, but whole-body insulin clearance was 23% higher and arterial insulin 16% lower in P1 versus P2 with GRI. Net hepatic glucose output was similar between treatments in P1. In P2, both treatments induced net hepatic glucose uptake (HGU) (HI mean ± SEM 2.1 ± 0.5 vs. 3.3 ± 0.4 GRI mg/kg/min). Nonhepatic glucose uptake in P1 and P2, respectively, differed between treatments (2.6 ± 0.3 and 7.4 ± 0.6 mg/kg/min with HI vs. 2.0 ± 0.2 and 8.1 ± 0.8 mg/kg/min with GRI). Thus, glycemia affected GRI but not HI clearance, with resultant differential effects on HGU and nonHGU. GRI holds promise for decreasing hypoglycemia risk while enhancing glucose uptake under hyperglycemic conditions.


Asunto(s)
Evaluación Preclínica de Medicamentos , Drogas en Investigación/efectos adversos , Metabolismo Energético/efectos de los fármacos , Hipoglucemiantes/efectos adversos , Insulina Regular Humana/análogos & derivados , Hígado/efectos de los fármacos , Absorción Fisiológica/efectos de los fármacos , Animales , Glucemia/análisis , Glucemia/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Drogas en Investigación/administración & dosificación , Drogas en Investigación/farmacocinética , Gluconeogénesis/efectos de los fármacos , Técnica de Clampeo de la Glucosa , Glicosilación , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/prevención & control , Hipoglucemia/inducido químicamente , Hipoglucemia/metabolismo , Hipoglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Infusiones Intravenosas , Insulina Regular Humana/administración & dosificación , Insulina Regular Humana/efectos adversos , Insulina Regular Humana/farmacocinética , Hígado/metabolismo , Masculino , Tasa de Depuración Metabólica , Distribución Aleatoria , Somatostatina/administración & dosificación , Somatostatina/efectos adversos
4.
ACS Med Chem Lett ; 7(5): 498-501, 2016 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-27190600

RESUMEN

In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.

5.
J Med Chem ; 47(10): 2441-52, 2004 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-15115388

RESUMEN

A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Indazoles/síntesis química , Pirazoles/síntesis química , Receptores de Glucocorticoides/metabolismo , Tiofenos/síntesis química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Línea Celular , Cristalografía por Rayos X , Inducción Enzimática , Femenino , Glutamato-Amoníaco Ligasa/biosíntesis , Glutamato-Amoníaco Ligasa/genética , Humanos , Indazoles/química , Indazoles/farmacología , Interleucina-6/antagonistas & inhibidores , Ligandos , Ratones , Ratones Endogámicos BALB C , Conformación Molecular , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Pirazoles/química , Pirazoles/farmacología , Ensayo de Unión Radioligante , Receptores de Glucocorticoides/agonistas , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Tirosina Transaminasa/biosíntesis , Tirosina Transaminasa/genética
6.
Bioorg Med Chem Lett ; 17(12): 3354-61, 2007 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-17467988

RESUMEN

Chemistry was developed to synthesize the title series of compounds. The ability of these novel ligands to bind to the glucocorticoid receptor was investigated. These compounds were also tested in a series of functional assays and some were found to display the profile of a dissociated glucocorticoid. The SAR of the 6,5-bicyclic series differed markedly from the previously reported 6,6-series. Molecular modeling studies were employed to understand the conformational differences between the two series of compounds, which may explain their divergent activity. Two compounds were profiled in vivo and shown to reduce inflammation in a mouse model. An active metabolite is suspected in one case.


Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos con Puentes/química , Glucocorticoides/química , Pirazoles/química , Receptores de Glucocorticoides/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Humanos , Ligandos , Ratones , Modelos Químicos , Modelos Moleculares , Receptores de Glucocorticoides/metabolismo , Relación Estructura-Actividad
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