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1.
J Med Chem ; 64(19): 14773-14792, 2021 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-34613725

RESUMEN

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , Enfermedades Metabólicas/tratamiento farmacológico , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Relación Estructura-Actividad
2.
J Med Chem ; 62(16): 7400-7416, 2019 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-31246024

RESUMEN

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.


Asunto(s)
Benzofuranos/farmacología , Fibrinolíticos/farmacología , Hemorragia/prevención & control , Receptores de Trombina/antagonistas & inhibidores , Trombosis/prevención & control , Animales , Benzofuranos/química , Benzofuranos/farmacocinética , Disponibilidad Biológica , Modelos Animales de Enfermedad , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Células HEK293 , Hemorragia/metabolismo , Humanos , Macaca fascicularis , Modelos Químicos , Estructura Molecular , Agregación Plaquetaria/efectos de los fármacos , Receptores de Trombina/genética , Receptores de Trombina/metabolismo , Relación Estructura-Actividad , Trombosis/metabolismo
3.
ACS Med Chem Lett ; 9(7): 673-678, 2018 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-30034599

RESUMEN

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.

4.
Anal Biochem ; 501: 48-55, 2016 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-26925857

RESUMEN

Monoacylglycerol acyltransferase 2 (MGAT2) is a membrane-bound lipid acyltransferase that catalyzes the formation of diacylglycerol using monoacylglycerol and fatty acyl CoA as substrates. MGAT2 is important for intestinal lipid absorption and is an emerging target for the treatment of metabolic diseases. In the current study, we identified and characterized four classes of novel MGAT2 inhibitors. We established both steady state and kinetic binding assay protocols using a novel radioligand, [(3)H]compound A. Diverse chemotypes of MGAT2 inhibitors were found to compete binding of [(3)H]compound A to MGAT2, indicating the broad utility of [(3)H]compound A for testing various classes of MGAT2 inhibitors. In the dynamic binding assays, the kinetic values of MGAT2 inhibitors such as Kon, Koff, and T1/2 were systematically defined. Of particular value, the residence times of inhibitors on MGAT2 enzyme were derived. We believe that the identification of novel classes of MGAT2 inhibitors and the detailed kinetic characterization provide valuable information for the identification of superior candidates for in vivo animal and clinical studies. The current work using a chemical probe to define inhibitory kinetics can be broadly applied to other membrane-bound acyltransferases.


Asunto(s)
Aciltransferasas/antagonistas & inhibidores , Aciltransferasas/metabolismo , Pruebas de Enzimas/métodos , Inhibidores Enzimáticos/farmacología , Animales , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/química , Humanos , Ligandos , Ratones , Unión Proteica/efectos de los fármacos , Ensayo de Unión Radioligante/métodos , Ratas , Proteínas Recombinantes/metabolismo
5.
Bioorg Med Chem Lett ; 25(4): 925-30, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25592713

RESUMEN

The structure-activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaffold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone (±)-24 factor XIa inhibitors. SAR and X-ray crystal structure data highlight the key differences between imidazole and six-membered ring analogs.


Asunto(s)
Factor XIa/antagonistas & inhibidores , Piridinas/farmacología , Piridonas/farmacología , Cristalografía por Rayos X , Modelos Moleculares , Relación Estructura-Actividad
6.
J Med Chem ; 57(23): 9915-32, 2014 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-25405503

RESUMEN

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.


Asunto(s)
Fibrinolíticos/síntesis química , Imidazoles/síntesis química , Indazoles/síntesis química , Animales , Cristalografía por Rayos X , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacología , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Indazoles/farmacocinética , Indazoles/farmacología , Modelos Moleculares , Tiempo de Tromboplastina Parcial , Conejos , Trombosis/prevención & control
7.
Bioorg Med Chem Lett ; 18(2): 474-8, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-18160281

RESUMEN

T-type calcium channel antagonists were designed using a protocol involving the program SPROUT and constrained by a ComFA-based pharmacophore model. Scaffolds generated by SPROUT were evaluated based on their ability to be translated into structures that were synthetically tractable. From this exercise, a novel series of potent and selective T-type channel antagonists containing a biaryl sulfonamide core were discovered.


Asunto(s)
Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Técnicas In Vitro , Técnicas de Placa-Clamp , Relación Estructura-Actividad
8.
Bioorg Med Chem Lett ; 15(20): 4579-84, 2005 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-16099653

RESUMEN

High affinity thyromimetics containing a novel phenyl-naphthylene core are reported. The functionalized core is readily accessible via a Suzuki coupling protocol. Examples of this new class of TR ligands have sub-nanomolar binding affinities for the TRbeta receptor and low to modest selectivity for TRbeta. They also exhibit an SAR that diverges from other thyromimetics that are based on the diaryl ether core found in 3,5,3'-triiodothyronine.


Asunto(s)
Naftalenos/química , Receptores de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/metabolismo , Modelos Moleculares , Relación Estructura-Actividad , Hormonas Tiroideas/química
9.
Bioorg Med Chem Lett ; 14(13): 3549-53, 2004 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-15177471

RESUMEN

A set of thyromimetics having improved selectivity for TR-beta1 were prepared by replacing the 3'-isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3'-phenyl moiety bearing small hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed with TR-beta1 LBD shows methionine 442 to be displaced by the bulky R3' phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand-receptor complex retains full agonist activity.


Asunto(s)
Receptores beta de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/química , Triyodotironina/química , 2-Propanol/química , Aminoácidos/química , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Diseño de Fármacos , Concentración 50 Inhibidora , Ligandos , Relación Estructura-Actividad , Receptores beta de Hormona Tiroidea/efectos de los fármacos , Hormonas Tiroideas/metabolismo , Hormonas Tiroideas/farmacología , Triyodotironina/metabolismo , Triyodotironina/farmacología
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