Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
1.
J Am Chem Soc ; 146(4): 2358-2363, 2024 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-38230893

RESUMEN

Dearomatization of pyridines is a well-established synthetic approach to access piperidines. Although remarkably powerful, existing dearomatization processes have been limited to the hydrogenation or addition of carbon-based nucleophiles to activated pyridiniums. Here, we show that arenophile-mediated dearomatizations can be applied to pyridines to directly introduce heteroatom functionalities without prior substrate activation. The arenophile platform in combination with olefin oxidation chemistry provides access to dihydropyridine cis-diols and epoxides. These previously elusive compounds are now readily accessible and can be used for the downstream preparation of diversely functionalized piperidines.

2.
Angew Chem Int Ed Engl ; 61(19): e202116775, 2022 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-35229419

RESUMEN

An efficient Pd-catalyzed one-pot desulfinative cross-coupling to access medicinally relevant di(hetero)arylmethanes is reported. The method is reductant-free, and involves a sulfinate transfer reagent and a Pd-catalyst mediating the union of two electrophilic coupling partners; a (hetero)aryl halide and a benzyl halide. We establish for the first time that benzyl sulfinates, generated in situ, undergo efficient Pd-catalyzed desulfinative cross-coupling with (hetero)aryl halides to generate di(hetero)arylmethanes. The reaction can be extended to benzylic pseudohalides derived from benzyl alcohols. The reactions are straightforward to perform and scalable, and all reaction components are commercially available.


Asunto(s)
Paladio , Sustancias Reductoras , Catálisis , Estructura Molecular
3.
Bioorg Med Chem ; 41: 116205, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34000509

RESUMEN

The ability to predict chemical structure from DNA sequence has to date been a necessary cornerstone of DNA-encoded library technology. DNA-encoded libraries (DELs) are typically screened by immobilized affinity selection and enriched library members are identified by counting the number of times an individual compound's sequence is observed in the resultant dataset. Those with high signal reads (DEL hits) are subsequently followed up through off-DNA synthesis of the predicted small molecule structures. However, hits followed-up in this manner often fail to translate to confirmed ligands. To address this low conversion rate of DEL hits to off-DNA ligands, we have developed an approach that eliminates the reliance on chemical structure prediction from DNA sequence. Here we describe our method of combining non-combinatorial resynthesis on-DNA following library procedures as a rapid means to assess the probable molecules attached to the DNA barcode. Furthermore, we apply our Bead-Assisted Ligand Isolation Mass Spectrometry (BALI-MS) technique to identify the true binders found within the mixtures of on-DNA synthesis products. Finally, we describe a Normalized Enrichment (NE) metric that allows for the quantitative assessment of affinity selection in these studies. We exemplify how this combined approach enables the identification of putative hit matter against a clinically relevant therapeutic target bisphosphoglycerate mutase, BPGM.


Asunto(s)
ADN/química , Descubrimiento de Drogas , Biblioteca de Genes , Espectrometría de Masas/métodos , Técnicas Químicas Combinatorias , Ligandos , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química
4.
Angew Chem Int Ed Engl ; 60(41): 22461-22468, 2021 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-34342107

RESUMEN

Heteroaromatic sulfinates are effective nucleophilic reagents in Pd0 -catalyzed cross-coupling reactions with aryl halides. However, metal sulfinate salts can be challenging to purify, solubilize in reaction media, and are not tolerant to multi-step transformations. Here we introduce base-activated, latent sulfinate reagents: ß-nitrile and ß-ester sulfones. We show that under the cross-coupling conditions, these species generate the sulfinate salt in situ, which then undergo efficient palladium-catalyzed desulfinative cross-coupling with (hetero)aryl bromides to deliver a broad range of biaryls. These latent sulfinate reagents have proven to be stable through multi-step substrate elaboration, and amenable to scale-up.

5.
J Am Chem Soc ; 140(46): 15916-15923, 2018 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-30412397

RESUMEN

Heterocyclic sulfinates are effective reagents in palladium-catalyzed coupling reactions with aryl and heteroaryl halides, often providing high yields of the targeted biaryl. However, the preparation and purification of complex heterocylic sulfinates can be problematic. In addition, sulfinate functionality is not tolerant of the majority of synthetic transformations, making these reagents unsuitable for multistep elaboration. Herein, we show that heterocyclic allylsulfones can function as latent sulfinate reagents and, when treated with a Pd(0) catalyst and an aryl halide, undergo deallylation, followed by efficient desulfinylative cross-coupling. A broad range of allyl heteroarylsulfones are conveniently prepared, using several complementary routes, and are shown to be effective coupling partners with a variety of aryl and heteroaryl halides. We demonstrate that the allylsulfone functional group can tolerate a range of standard synthetic transformations, including orthogonal C- and N-coupling reactions, allowing multistep elaboration. The allylsulfones are successfully coupled with a variety of medicinally relevant substrates, demonstrating their applicability in demanding cross-coupling transformations. In addition, pharmaceutical agents crizotinib and etoricoxib were prepared using allyl heteroaryl sulfone coupling partners, further demonstrating the utility of these new reagents.

6.
J Pharmacol Exp Ther ; 361(2): 303-311, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28289077

RESUMEN

Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the ß1 subunit. After confirming that human and rodent kidney predominately express AMPK ß1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Aminopiridinas/farmacología , Nefropatías Diabéticas/tratamiento farmacológico , Activadores de Enzimas/farmacología , Indoles/farmacología , Riñón/efectos de los fármacos , Aminopiridinas/uso terapéutico , Animales , Tamaño de la Célula , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Activación Enzimática , Fibrosis , Humanos , Indoles/uso terapéutico , Isoenzimas/metabolismo , Riñón/metabolismo , Riñón/patología , Pruebas de Función Renal , Macaca fascicularis , Ratones Endogámicos C57BL , Estrés Oxidativo , Fosforilación , Proteinuria/tratamiento farmacológico , Proteinuria/metabolismo , Ratas , Especificidad de la Especie
7.
Angew Chem Int Ed Engl ; 54(46): 13571-5, 2015 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-26383866

RESUMEN

A palladium-catalyzed one-step synthesis of (hetero)aryl alkyl sulfones from (hetero)arylboronic acids, potassium metabisulfite, and unactivated or activated alkylhalides is described. This transformation is of broad scope, occurs under mild conditions, and employs readily available reactants. A stoichiometric experiment has led to the isolation of a catalytically active dimeric palladium sulfinate complex, which was characterized by X-ray diffraction analysis.


Asunto(s)
Ácidos Borónicos/química , Hidrocarburos Halogenados/química , Compuestos Organometálicos/química , Paladio/química , Sulfitos/química , Sulfonas/síntesis química , Catálisis , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Sulfonas/química
8.
Org Lett ; 26(14): 2702-2707, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-37094230

RESUMEN

C(sp3)-rich aliphatic motifs in drug molecules are strongly associated with clinical success. Historically, the availability of compound libraries based on C(sp3)-rich cores has been limited due to the challenging direct functionalization of aliphatic rings. Instead, most small molecule drug-like libraries are diversified around central aromatic rings. Herein, we present a general approach to the synthesis of diversified libraries featuring aliphatic core rings via photoredox catalysis under mild conditions.


Asunto(s)
Química Farmacéutica , Catálisis
9.
Org Lett ; 26(14): 2817-2820, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38189248

RESUMEN

Catalysis using substoichiometric copper facilitates the synthesis of masked (hetero)aryl sulfinates under mild, base-free conditions from aryl iodides and the commercial sulfonylation reagent sodium 1-methyl 3-sulfinopropanoate (SMOPS). The development of a tert-butyl ester variant of the SMOPS reagent allowed the use of aryl bromide substrates. The sulfones thus generated can be unmasked and functionalized in situ to form a variety of sulfonyl-containing functional groups.

10.
J Med Chem ; 63(22): 13546-13560, 2020 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-32910646

RESUMEN

Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.


Asunto(s)
Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/química , Fructoquinasas/antagonistas & inhibidores , Fructoquinasas/metabolismo , Fructosa/efectos adversos , Enfermedades Metabólicas/enzimología , Animales , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Fructosa/administración & dosificación , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Resistencia a la Insulina/fisiología , Masculino , Enfermedades Metabólicas/inducido químicamente , Enfermedades Metabólicas/tratamiento farmacológico , Estructura Secundaria de Proteína , Ratas , Ratas Wistar
11.
J Med Chem ; 63(19): 10879-10896, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-32809824

RESUMEN

Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.


Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/farmacología , Hígado/efectos de los fármacos , Acetil-CoA Carboxilasa/metabolismo , Animales , Inhibidores Enzimáticos/uso terapéutico , Humanos , Lipogénesis , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Especificidad por Sustrato
12.
ACS Med Chem Lett ; 9(5): 440-445, 2018 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-29795756

RESUMEN

Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary phosphate excretion and correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease-mineral and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. Herein, we detail the discovery of the first series of selective NaPi2a inhibitors, resulting from optimization of a high-throughput screening hit. The oral PK profile of inhibitor PF-06869206 (6f) in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.

13.
ACS Med Chem Lett ; 9(2): 125-130, 2018 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-29456800

RESUMEN

Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4, this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-molecule ROMK inhibitors, members of this series were demonstrated to be highly selective for inhibition of human over rat ROMK and to be insensitive to the N171D pore mutation that abolishes inhibitory activity of previously reported ROMK inhibitors.

14.
J Med Chem ; 61(6): 2372-2383, 2018 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-29466005

RESUMEN

Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.


Asunto(s)
Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Activadores de Enzimas/síntesis química , Activadores de Enzimas/farmacología , Indoles/síntesis química , Indoles/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Activadores de Enzimas/farmacocinética , Humanos , Indoles/farmacocinética , Absorción Intestinal , Riñón/efectos de los fármacos , Riñón/enzimología , Masculino , Modelos Moleculares , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Ratas , Ratas Wistar , Relación Estructura-Actividad
15.
J Med Chem ; 60(18): 7835-7849, 2017 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-28853885

RESUMEN

Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.


Asunto(s)
Diseño de Fármacos , Fructoquinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Cristalografía por Rayos X , Fructoquinasas/química , Fructoquinasas/metabolismo , Humanos , Masculino , Simulación del Acoplamiento Molecular , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley
16.
Org Lett ; 18(22): 5848-5851, 2016 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-27788009

RESUMEN

An efficient methodology has been developed for the one-pot or telescoped synthesis of aliphatic sulfonamides, sulfonyl fluorides, and unsymmetrical sulfones on the basis of interrupted alkylation of sodium hydroxymethylsulfinate (rongalite) with alkyl halides. The protocols are conducted under mild conditions, use inexpensive and shelf-stable reagents, and are not sensitive to air/moisture. These conditions can be applied in rapid parallel chemical synthesis, which was demonstrated by the preparation of a small sulfonamide library based on the core structure of the anticoagulant drug Tirofiban.

17.
J Med Chem ; 59(17): 8068-81, 2016 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-27490827

RESUMEN

Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Activadores de Enzimas/química , Indoles/química , Administración Oral , Adsorción , Animales , Cristalografía por Rayos X , Perros , Activadores de Enzimas/síntesis química , Activadores de Enzimas/farmacocinética , Activadores de Enzimas/farmacología , Ensayos Analíticos de Alto Rendimiento , Humanos , Indazoles/síntesis química , Indazoles/química , Indazoles/farmacología , Indoles/síntesis química , Indoles/farmacocinética , Indoles/farmacología , Inyecciones Intravenosas , Macaca fascicularis , Masculino , Modelos Moleculares , Conformación Proteica , Ratas
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA