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1.
J Org Chem ; 87(22): 15559-15563, 2022 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-36259765

RESUMEN

A concise strategy for the total synthesis of several Aspidosperma alkaloids is reported. A Suzuki-Miyaura cross-coupling provides access to a 2-vinyl indole that undergoes a Diels-Alder cascade reaction with butyn-2-one to deliver a pyrroloindoline intermediate. This undergoes cascade amidation, reduction, skeletal rearrangement, and intramolecular Michael addition to provide a common intermediate containing the full framework of the Aspidosperma alkaloids. The utility of this intermediate is shown in the synthesis of four different natural products.


Asunto(s)
Alcaloides , Aspidosperma , Alcaloides Indólicos , Estereoisomerismo
2.
Bioorg Med Chem Lett ; 30(9): 127106, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32184044

RESUMEN

Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Quinasa 6 Dependiente de la Ciclina/metabolismo , Diseño de Fármacos , Ubiquitina-Proteína Ligasas/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Antineoplásicos/química , Quinasa 4 Dependiente de la Ciclina/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células Jurkat , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacología , Inhibidores de Proteasoma/farmacología , Ubiquitina-Proteína Ligasas/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética
3.
Org Biomol Chem ; 14(25): 5992-6009, 2016 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-27226381

RESUMEN

A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).


Asunto(s)
Ácido Butírico/síntesis química , Ácido Butírico/farmacología , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Integrinas/antagonistas & inhibidores , Pirrolidinas/química , Pirrolidinas/farmacología , Antígenos de Neoplasias , Ácido Butírico/química , Ácido Butírico/uso terapéutico , Técnicas de Química Sintética , Oxidación-Reducción , Pirrolidinas/síntesis química , Pirrolidinas/uso terapéutico , Estereoisomerismo
4.
Chemistry ; 21(24): 8951-64, 2015 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-25959852

RESUMEN

Boronic acid solution speciation can be controlled during the Suzuki-Miyaura cross-coupling of haloaryl N-methyliminodiacetic acid (MIDA) boronic esters to enable the formal homologation of boronic acid derivatives. The reaction is contingent upon control of the basic biphase and is thermodynamically driven: temperature control provides highly chemoselective access to either BMIDA adducts at room temperature or boronic acid pinacol ester (BPin) products at elevated temperature. Control experiments and solubility analyses have provided some insight into the mechanistic operation of the formal homologation process.


Asunto(s)
Ácidos Borónicos/química , Ésteres/química , Catálisis , Estructura Molecular
5.
J Med Chem ; 65(22): 15174-15207, 2022 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-36378954

RESUMEN

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.


Asunto(s)
Lisina , Factores de Transcripción , Humanos , Lisina/metabolismo , Ligandos , Dominios Proteicos , Histonas/metabolismo
6.
J Med Chem ; 64(18): 13780-13792, 2021 09 23.
Artículo en Inglés | MEDLINE | ID: mdl-34510892

RESUMEN

Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Sulfonamidas/farmacología , Animales , Cristalografía por Rayos X , Femenino , Masculino , Ratones Endogámicos BALB C , Estructura Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3/metabolismo , Unión Proteica , Ratas Wistar , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/metabolismo
7.
ACS Med Chem Lett ; 10(7): 1081-1085, 2019 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-31312412

RESUMEN

Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a key mediator of innate immunity. IRAK4 overactivation is linked with several autoimmune diseases. To date, many IRAK4 inhibitors have been developed to block the protein's kinase activity with the most advanced reaching Phase II clinical trials. Nevertheless, several reports suggest kinase activity is not disease-relevant in certain cell types, so removing scaffolding signaling in addition to IRAK4 kinase activity may offer a better therapeutic outcome. Herein, we describe the design and synthesis of an IRAK4 Proteolysis Targeted Chimera (PROTAC). We show that IRAK4 degradation induced by compound 9 leads to the inhibition of multiple cytokines in PBMCs. However, in IL-1ß stimulated human dermal fibroblasts, inhibition of IL-6 and TNF-α release was not observed despite IRAK4 degradation. Nonetheless, the possibility of targeting both IRAK4 kinase and scaffolding function could potentially lead to new therapeutic opportunities to treat autoimmune, inflammatory, and oncological diseases.

8.
J Med Chem ; 62(19): 8796-8808, 2019 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-31497959

RESUMEN

The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvß3 and αvß5 significantly change the biological activities against αvß6 and αvß8. This resulted in the discovery of a pan αv antagonist (compound 39, 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).


Asunto(s)
Fibrosis Pulmonar Idiopática/patología , Integrina alfaV/química , Fenilbutiratos/química , Administración Oral , Animales , Antígenos de Neoplasias/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/metabolismo , Integrina alfaV/metabolismo , Integrina alfaVbeta3/antagonistas & inhibidores , Integrina alfaVbeta3/metabolismo , Integrinas/antagonistas & inhibidores , Integrinas/metabolismo , Conformación Molecular , Simulación del Acoplamiento Molecular , Fenilbutiratos/farmacocinética , Fenilbutiratos/uso terapéutico , Estructura Terciaria de Proteína , Ratas , Receptores de Vitronectina/antagonistas & inhibidores , Receptores de Vitronectina/metabolismo , Relación Estructura-Actividad
9.
J Med Chem ; 62(10): 5096-5110, 2019 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-31013427

RESUMEN

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.


Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas de Complejo Poro Nuclear/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Proteínas de Unión al ARN/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Línea Celular , Enfermedad Crónica , Diseño de Fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Haplorrinos , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Esclerosis Múltiple/tratamiento farmacológico , Pirazoles/farmacocinética , Ratas , Retinitis Pigmentosa/tratamiento farmacológico , Relación Estructura-Actividad
10.
J Med Chem ; 61(18): 8417-8443, 2018 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-30215258

RESUMEN

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αvß1, αvß3, αvß5, αvß6, and αvß8 integrins. Numerous analogs with high affinity and selectivity for the αvß6 integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αvß6 integrin in a radioligand binding assay (p Ki = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.


Asunto(s)
Descubrimiento de Drogas , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Integrinas/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Pirazoles/química , Animales , Antígenos de Neoplasias , Adhesión Celular , Perros , Humanos , Pulmón/metabolismo , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Ratas , Ratas Wistar , Relación Estructura-Actividad , Distribución Tisular
11.
Org Lett ; 19(23): 6368-6371, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29135268

RESUMEN

Functionalized bicyclic amino-azaheterocycles are rapidly accessed in a one-pot cross-coupling/reduction sequence enabled by the use of COware. Incompatible reagents are physically separated in a single reaction vessel to effect two chemoselective transformations-Suzuki-Miyaura cross-coupling and heteroarene reduction. The developed method allows access to novel heterocyclic templates, including semisaturated Hedgehog and dual PI3K/mTOR inhibitors, which show enhanced physicochemical properties compared to their unsaturated counterparts.

12.
Chem Sci ; 8(2): 1551-1559, 2017 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-28572912

RESUMEN

We report the direct chemoselective Brown-type oxidation of aryl organoboron systems containing two oxidizable boron groups. Basic biphasic reaction conditions enable selective formation and phase transfer of a boronic acid trihydroxyboronate in the presence of boronic acid pinacol (BPin) esters, while avoiding speciation equilibria. Spectroscopic investigations validate a base-promoted phase-selective discrimination of organoboron species. This phenomenon is general across a broad range of organoboron compounds and can also be used to invert conventional protecting group strategies, enabling chemoselective oxidation of BMIDA species over normally more reactive BPin substrates. We also demonstrate the selective oxidation of diboronic acid systems with chemoselectivity predictable a priori. The utility of this method is exemplified through the development of a chemoselective oxidative nucleophile coupling.

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