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1.
J Chem Inf Model ; 60(11): 5457-5474, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-32813975

RESUMO

Accurate ranking of compounds with regards to their binding affinity to a protein using computational methods is of great interest to pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way to estimate binding affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present the results of large-scale prospective application of the FEP+ method in active drug discovery projects in an industry setting at Merck KGaA, Darmstadt, Germany. We compare these prospective data to results obtained on a new diverse, public benchmark of eight pharmaceutically relevant targets. Our results offer insights into the challenges faced when using free energy calculations in real-life drug discovery projects and identify limitations that could be tackled by future method development. The new public data set we provide to the community can support further method development and comparative benchmarking of free energy calculations.


Assuntos
Descoberta de Drogas , Ligantes , Estudos Prospectivos , Estudos Retrospectivos , Termodinâmica
2.
Angew Chem Int Ed Engl ; 55(20): 6093-8, 2016 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-27062726

RESUMO

In the presence of trialkylaluminum reagents, diverse aryl methyl ethers can be transformed into valuable products by C-O bond-cleaving alkylation, for the first time without the limiting ß-hydride elimination. This new nickel-catalyzed dealkoxylative alkylation method enables powerful orthogonal synthetic strategies for the transformation of a variety of naturally occurring and easily accessible anisole derivatives. The directing and/or activating properties of aromatic methoxy groups are utilized first, before they are replaced by alkyl chains in a subsequent coupling process.

3.
Angew Chem Int Ed Engl ; 53(47): 12912-5, 2014 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-25250516

RESUMO

The direct replacement of aromatic methoxy groups with activated carbon nucleophiles would give rise to novel synthetic pathways for targeted and diversity-oriented syntheses. We demonstrate here that this transformation can be achieved in a one-step reaction involving a bifunctional organolithium nucleophile in combination with a CAr OMe bond-cleaving nickel catalyst. The resulting products are stable, α-CH active, and suitable for various further modifications.

4.
J Med Chem ; 66(1): 837-854, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36516476

RESUMO

The highly conserved catalytic sites in protein kinases make it difficult to identify ATP competitive inhibitors with kinome-wide selectivity. Serendipitously, during a dedicated fragment campaign for the focal adhesion kinase (FAK), a scaffold that had lost its initial FAK affinity showed remarkable potency and selectivity for serine-arginine-protein kinases 1-3 (SRPK1-3). Non-conserved interactions with the uniquely structured hinge region of the SRPK family were the key drivers of the exclusive selectivity of the discovered fragment hit. Structure-guided medicinal chemistry efforts led to the SRPK inhibitor MSC-1186, which fulfills all hallmarks of a reversible chemical probe, including nanomolar cellular potency and excellent kinome-wide selectivity. The combination of MSC-1186 with CDC2-like kinase (CLK) inhibitors showed additive attenuation of SR-protein phosphorylation compared to the single agents. MSC-1186 and negative control (MSC-5360) are chemical probes available via the Structural Genomics Consortium chemical probe program (https://www.sgc-ffm.uni-frankfurt.de/).


Assuntos
Proteínas Serina-Treonina Quinases , Pirimidinas , Fosforilação , Pirimidinas/farmacologia , Benzimidazóis/farmacologia
5.
J Med Chem ; 66(13): 8666-8686, 2023 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-37403966

RESUMO

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2α has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2α PAS B domain, can alter its conformation and disturb the activity of the HIF dimer complex. Herein, the design, synthesis, and systematic SAR exploration of cycloalkyl[c]thiophenes as novel HIF-2α inhibitors are described, providing the first chemotype featuring an alkoxy-aryl scaffold. X-ray data confirmed the ability of these inhibitors to induce perturbation of key amino acids by appropriately presenting key pharmacophoric elements in the hydrophobic cavity. Selected compounds showed inhibition of VEGF-A secretion in cancer cells and prevention of Arg1 expression and activity in IL4-stimulated macrophages. Moreover, in vivo target gene modulation was demonstrated with compound 35r. Thus, the disclosed HIF-2α inhibitors represent valuable tools for investigating selective HIF-2α inhibition and its effect on tumor biology.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Tiofenos , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Tiofenos/farmacologia , Fatores de Transcrição , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia
6.
Org Lett ; 20(18): 5644-5647, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30168331

RESUMO

A nickel-catalyzed cross coupling of aryl fluorides via C-F bond activation has been developed. The alkylation method allows selective replacement of aryl fluorides by alkyl groups and enables the synthesis of diverse and otherwise difficult to access scaffolds in good yields.

7.
ACS Med Chem Lett ; 7(10): 944-949, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27774134

RESUMO

Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC50 = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.

8.
Chem Commun (Camb) ; 51(10): 1937-40, 2015 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-25532100

RESUMO

The application of cyclic and acyclic enol ethers as electrophiles in cross coupling reactions offers new possibilities for the preparation of functional compounds. A novel nickel catalyzed dealkoxylative cross coupling reaction allows access to structurally diverse allylsilanes and alcohol derivatives with high stereospecificity and in good yields under mild reaction conditions directly from the corresponding enol ethers.

9.
Macromolecules ; 45(3): 1254-1261, 2012 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23599541

RESUMO

Conventional synthesis of polymers by ATRP is relatively low throughput, involving iterative optimization of conditions in an inert atmosphere. Automated, high-throughput controlled radical polymerization was developed to accelerate catalyst optimization and production of disulfide-functionalized polymers without the need of an inert gas. Using ARGET ATRP, polymerization conditions were rapidly identified for eight different monomers, including the first ARGET ATRP of 2-(diethylamino)ethyl methacrylate and di(ethylene glycol) methyl ether methacrylate. In addition, butyl acrylate, oligo(ethylene glycol) methacrylate 300 and 475, 2-(dimethylamino)ethyl methacrylate, styrene, and methyl methacrylate were polymerized using bis(2-hydroxyethyl) disulfide bis(2-bromo-2-methylpropionate) as the initiator, tris(2-pyridylmethyl)amine as the ligand, and tin(II) 2-ethylhexanoate as the reducing agent. The catalyst and reducing agent concentration was optimized specifically for each monomer, and then a library of polymers was synthesized systematically using the optimized conditions. The disulfide-functionalized chains could be cleaved to two thiol-terminated chains upon exposure to dithiothreitol, which may have utility for the synthesis of polymer bioconjugates. Finally, we demonstrated that these new conditions translated perfectly to conventional batch polymerization. We believe the methods developed here may prove generally useful to accelerate the systematic optimization of a variety of chemical reactions and polymerizations.

10.
Chem Commun (Camb) ; 47(38): 10629-31, 2011 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-21892507

RESUMO

A transition metal-free Heck-type cyclization/isomerization reaction has been developed. Mediated by potassium tert-butoxide and phenanthroline a variety of benzofuran derivatives have been synthesized.

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