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1.
J Biol Chem ; 297(2): 100928, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34274316

RESUMO

B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 µg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.


Assuntos
Proteínas Proto-Oncogênicas c-bcl-6 , Animais , Linfócitos B/metabolismo , Humanos , Camundongos , Transcrição Gênica , Dedos de Zinco
2.
Chemistry ; 26(14): 3026-3029, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-31922300

RESUMO

A radical domino cyclisation reaction of N-cyanamide alkenes, mediated by hydrogen atom transfer (HAT) has been developed. This method, using PhSiH3 and catalytic Fe(acac)3 , allows for the synthesis of challenging (spiro)quinazolinone scaffolds from simple, tractable (hetero)aryl carboxylic acid and cyanamide building blocks.

3.
Bioorg Med Chem Lett ; 30(21): 127533, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32919012

RESUMO

Structure-based led optimisation of orally active reversible Methionine Aminopeptidase-2 (MetAP-2) inhibitors utilising a 'molecular budget' medicinal chemistry strategy is described. The key physicochemical parameters of target molecules (cLogP, molecular size and H-bond donor count) were monitored through straightforward and intuitive use of atom count and distribution. The balance between structure-based design and an awareness of the physicochemical properties of the compounds synthesised enabled the rapid identification of a potent molecule with good oral pharmacokinetic (PK) characteristics by making fewer, higher quality compounds. The resulting candidate quality molecule was validated in a mechanistic cellular assay and a rodent secondary immunisation model.


Assuntos
Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Metionil Aminopeptidases/antagonistas & inibidores , Química Farmacêutica , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indóis/síntese química , Indóis/química , Metionil Aminopeptidases/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
4.
Chemistry ; 24(70): 18658-18662, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30341926

RESUMO

Hydrogen atom transfer-mediated intramolecular C-C coupling reactions between alkenes and nitriles, using PhSiH3 and catalytic Fe(acac)3 , are described. This introduces a new strategic bond disconnection for ring-closing reactions, forming ketones via imine intermediates. Of note is the scope of the reaction, including formation of sterically hindered ketones, spirocycles and fused cyclic systems.

5.
J Org Chem ; 83(16): 8888-8905, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29978696

RESUMO

The intramolecular carbocyclization of difluorinated enol acetals has been achieved for the first time using gold(I) catalysis. Difluorinated enol acetals bearing a pendant alkene group can be cyclized and reduced in one pot to form fluorinated diol motifs. Alternatively, the cyclization of terminal alkynes allows for the synthesis of fluorinated pyran scaffolds. Both cyclization processes can be performed under mild conditions allowing access to complex products rich in functionality. The cyclic systems are synthesized concisely (maximum four steps) from trifluoroethanol, an inexpensive fluorinated feedstock.

6.
Chemistry ; 21(52): 19119-27, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26564395

RESUMO

Palladium(II)-catalysed cycloalkenylation (Saegusa-Ito cyclisation) has been used for the first time to transform difluorinated silylenol ethers to difluorinated cycloalkenones under mild conditions. The silylenol ether precursors were prepared in two high-yielding steps from trifluoroethanol, and cyclised in moderate to good yields. A combination of air and copper(I) chloride in acetonitrile gave the turnover of the initial palladium(II) salt, whereas the provision of an oxygen atmosphere ensured more rapid reaction. Annulations required a minimum level of substitution on the chain, but failed when the alkene was substituted. Annelations allowed a range of n,6-bicyclic systems to be prepared and afforded three products, in which heterocycles were fused to the new cyclohexenone. The least substituted system explored underwent cyclisation followed by terminal oxidation to a cyclic enal, which corresponded to a Wacker product of unusual regiochemistry.

7.
Org Biomol Chem ; 13(10): 3093-102, 2015 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-25628154

RESUMO

A modular synthesis of functionalised biaryl phenols from two boronic acid derivatives has been developed via one-pot Suzuki-Miyaura cross-coupling, chemoselective control of boron solution speciation to generate a reactive boronic ester in situ, and oxidation. The utility of this method has been further demonstrated by application in the synthesis of drug molecules and components of organic electronics, as well as within iterative cross-coupling.


Assuntos
Boro/química , Fenóis/química , Fenóis/síntese química , Catálise , Desenho de Fármacos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxidantes/química , Oxigênio/química , Fenol/química , Solventes/química , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo
8.
J Med Chem ; 67(12): 10464-10489, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38866424

RESUMO

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.


Assuntos
Administração Intravenosa , Animais , Administração Oral , Camundongos , Relação Estrutura-Atividade , Humanos , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Estrutura Molecular
9.
Chem Commun (Camb) ; 58(21): 3509-3512, 2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35195133

RESUMO

We describe a catalytic system for the conversion of carboxylic acids into alcohols using substoichiometric zinc acetate and N-methyl morpholine, in combination with phenylsilane as the nominal terminal reductant. Reaction monitoring by 19F NMR spectroscopy demonstrates that the reaction proceeds by mutual activation of the carboxylic acid and silane through the in situ generation of silyl ester intermediates.

10.
J Med Chem ; 65(22): 15174-15207, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36378954

RESUMO

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.


Assuntos
Lisina , Fatores de Transcrição , Humanos , Lisina/metabolismo , Ligantes , Domínios Proteicos , Histonas/metabolismo
11.
J Med Chem ; 65(3): 2262-2287, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34995458

RESUMO

Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free-Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.


Assuntos
Aminoquinolinas/química , Desenho de Fármacos , Proteínas/metabolismo , Administração Oral , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacocinética , Aminoquinolinas/uso terapêutico , Animais , Benzoatos/química , Benzoatos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Cães , Meia-Vida , Humanos , Masculino , Camundongos , Conformação Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Proteínas/antagonistas & inibidores , Ratos , Relação Estrutura-Atividade
12.
Chem Sci ; 11(35): 9494-9500, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34123174

RESUMO

We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.

13.
J Med Chem ; 63(2): 714-746, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31904959

RESUMO

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Proteínas/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Quimiocina CCL2/biossíntese , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas
14.
FEBS J ; 286(20): 3998-4023, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31177613

RESUMO

Malarial dipeptidyl aminopeptidases (DPAPs) are cysteine proteases important for parasite development thus making them attractive drug targets. In order to develop inhibitors specific to the parasite enzymes, it is necessary to map the determinants of substrate specificity of the parasite enzymes and its mammalian homologue cathepsin C (CatC). Here, we screened peptide-based libraries of substrates and covalent inhibitors to characterize the differences in specificity between parasite DPAPs and CatC, and used this information to develop highly selective DPAP1 and DPAP3 inhibitors. Interestingly, while the primary amino acid specificity of a protease is often used to develop potent inhibitors, we show that equally potent and highly specific inhibitors can be developed based on the sequences of nonoptimal peptide substrates. Finally, our homology modelling and docking studies provide potential structural explanations of the differences in specificity between DPAP1, DPAP3, and CatC, and between substrates and inhibitors in the case of DPAP3. Overall, this study illustrates that focusing the development of protease inhibitors solely on substrate specificity might overlook important structural features that can be exploited to develop highly potent and selective compounds.


Assuntos
Aminoácidos/química , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Eritrócitos/parasitologia , Malária Falciparum/parasitologia , Fragmentos de Peptídeos/metabolismo , Plasmodium falciparum/crescimento & desenvolvimento , Inibidores de Proteases/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/metabolismo , Modelos Moleculares , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Conformação Proteica , Especificidade por Substrato
15.
J Med Chem ; 61(10): 4317-4334, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29656650

RESUMO

The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.


Assuntos
Descoberta de Drogas , Proteínas Nucleares/antagonistas & inibidores , Domínios e Motivos de Interação entre Proteínas , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinoxalinas/química , Quinoxalinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Proteínas de Ciclo Celular , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Homologia de Sequência
16.
Org Lett ; 9(23): 4901-4, 2007 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-17924643

RESUMO

A broadly applicable oxidative coupling strategy of 3-substituted catechols and carbon-centered pro-nucleophiles for the construction of arylated quaternary stereogenic centers has been developed. Pivoting on a base-catalyzed addition of a carbon-centered acid to an in situ generated o-benzoquinone, the method is general and atom-economical and provides remarkably efficient access to one of the most challenging structural motifs. Furthermore, use of chiral bifunctional organocatalysts allows the process to be rendered asymmetric (up to 81% ee).


Assuntos
Compostos Orgânicos/química , Benzoquinonas/química , Produtos Biológicos/química , Catálise , Catecóis/química , Modelos Químicos , Estrutura Molecular , Oxirredução , Fenilacetatos/química , Estereoisomerismo
17.
ACS Med Chem Lett ; 8(1): 43-48, 2017 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-28105273

RESUMO

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

18.
J Med Chem ; 59(3): 1003-20, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26751273

RESUMO

FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines.


Assuntos
Descoberta de Drogas , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Linhagem Celular , Cães , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Receptores de Esfingosina-1-Fosfato , Relação Estrutura-Atividade
19.
Org Lett ; 12(6): 1252-4, 2010 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-20175516

RESUMO

The total synthesis of (+/-)-powelline (13 linear steps in an overall yield of 6%) and (+/-)-buphanidrine (14 linear steps and a 6% overall yield) and has been achieved using a novel approach to the crinane skeleton. An organocatalytic oxidative coupling allowed direct construction of the key quaternary carbon-to-aryl bond in high yield allowing rapid access to the target alkaloids.


Assuntos
Liliaceae/química , Fenantridinas/síntese química , Alcaloides de Amaryllidaceae , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Fenantridinas/química , Estereoisomerismo
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