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1.
Nature ; 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38843825

RESUMO

The ability to tame high-energy intermediates is critical for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often elusive, high-energy intermediates.1,2 Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the critical carbon-metal bond. However, these methods are often prohibitive due to reagent safety concerns, limiting their broad implementation in synthesis.3-6 Mechanistically, an alternative approach to carbene intermediates that could circumvent these pitfalls would involve two single-electron steps: radical addition to a metal to forge the initial carbon-metal bond followed by redox-promoted α-elimination to yield the desired metal carbene intermediate. Herein, this strategy is realized through a metallaphotoredox platform that exploits iron carbene reactivity using readily available chemical feedstocks as radical sources and α-elimination from six classes of previously underexploited leaving groups. These discoveries permit cyclopropanation and σ-bond insertion into N-H, S-H, and P-H bonds from abundant and bench-stable carboxylic acids, amino acids, and alcohols, thereby providing a general solution to the challenge of carbene-mediated chemical diversification.

2.
Nature ; 628(8007): 326-332, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38480891

RESUMO

Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts1-3. In particular, semisaturated heteroarenes possess attractive solubility properties and a higher fraction of sp3 carbons, which can improve binding affinity and specificity. However, these desirable structures remain rare owing to limitations in current synthetic methods4-6. Indeed, semisaturated heterocycles are laboriously prepared by means of non-modular fit-for-purpose syntheses, which decrease throughput, limit chemical diversity and preclude their inclusion in many hit-to-lead campaigns7-10. Herein, we describe a more intuitive and modular couple-close approach to build semisaturated ring systems from dual radical precursors. This platform merges metallaphotoredox C(sp2)-C(sp3) cross-coupling with intramolecular Minisci-type radical cyclization to fuse abundant heteroaryl halides with simple bifunctional feedstocks, which serve as the diradical synthons, to rapidly assemble a variety of spirocyclic, bridged and substituted saturated ring types that would be extremely difficult to make by conventional methods. The broad availability of the requisite feedstock materials allows sampling of regions of underexplored chemical space. Reagent-controlled radical generation leads to a highly regioselective and stereospecific annulation that can be used for the late-stage functionalization of pharmaceutical scaffolds, replacing lengthy de novo syntheses.


Assuntos
Carbono , Técnicas de Química Sintética , Compostos Heterocíclicos com 1 Anel , Preparações Farmacêuticas , Carbono/química , Ciclização , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Solubilidade , Oxirredução , Fotoquímica , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Técnicas de Química Sintética/métodos
3.
ACS Med Chem Lett ; 14(9): 1179-1187, 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37736184

RESUMO

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and are frequently altered in cancer cells, thereby leading to uncontrolled proliferation. In this context, CDK2 has emerged as an appealing target for anticancer drug development. Herein, we describe the discovery of a series of selective small molecule inhibitors of CDK2 beginning with historical compounds from our ERK2 program (e.g., compound 6). Structure-based drug design led to the potent and selective tool compound 32, where excellent selectivity against ERK2 and CDK4 was achieved by filling the lipophilic DFG-1 pocket and targeting interactions with CDK2-specific lower hinge binding residues, respectively. Compound 32 demonstrated 112% tumor growth inhibition in mice bearing OVCAR3 tumors with 50 mg/kg bis in die (BID) oral dosing.

4.
Sci Signal ; 13(634)2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32487715

RESUMO

The dysregulation of multiple signaling pathways, including those through endosomal Toll-like receptors (TLRs), Fc gamma receptors (FcγR), and antigen receptors in B cells (BCR), promote an autoinflammatory loop in systemic lupus erythematosus (SLE). Here, we used selective small-molecule inhibitors to assess the regulatory roles of interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) and Bruton's tyrosine kinase (BTK) in these pathways. The inhibition of IRAK4 repressed SLE immune complex- and TLR7-mediated activation of human plasmacytoid dendritic cells (pDCs). Correspondingly, the expression of interferon (IFN)-responsive genes (IRGs) in cells and in mice was positively regulated by the kinase activity of IRAK4. Both IRAK4 and BTK inhibition reduced the TLR7-mediated differentiation of human memory B cells into plasmablasts. TLR7-dependent inflammatory responses were differentially regulated by IRAK4 and BTK by cell type: In pDCs, IRAK4 positively regulated NF-κB and MAPK signaling, whereas in B cells, NF-κB and MAPK pathways were regulated by both BTK and IRAK4. In the pristane-induced lupus mouse model, inhibition of IRAK4 reduced the expression of IRGs during disease onset. Mice engineered to express kinase-deficient IRAK4 were protected from both chemical (pristane-induced) and genetic (NZB/W_F1 hybrid) models of lupus development. Our findings suggest that kinase inhibitors of IRAK4 might be a therapeutic in patients with SLE.


Assuntos
Células Dendríticas/metabolismo , Endossomos/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Glicoproteínas de Membrana/metabolismo , Plasmócitos/metabolismo , Transdução de Sinais , Receptor 7 Toll-Like/metabolismo , Tirosina Quinase da Agamaglobulinemia , Animais , Endossomos/genética , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Glicoproteínas de Membrana/genética , Camundongos , Receptor 7 Toll-Like/genética
5.
ACS Med Chem Lett ; 11(3): 327-333, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32184965

RESUMO

IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent molecule 19 that achieves robust in vivo inhibition of cytokines relevant to human disease.

6.
J Med Chem ; 62(13): 6223-6240, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31082230

RESUMO

A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacologia , Animais , Benzofuranos/síntese química , Benzofuranos/metabolismo , Benzofuranos/farmacologia , Domínio Catalítico , Feminino , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
7.
J Med Chem ; 61(20): 9030-9058, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-29870256

RESUMO

Small molecule inhibitors targeting autoimmune and inflammatory processes have been an area of intense focus within academia and industry. Much of this work has been aimed at key kinases operating as central nodes in inflammatory signaling pathways. While this focus has led to over 30 FDA-approved small molecule kinase inhibitors, only one is currently approved for autoimmune and inflammatory diseases. Despite this lack of success, there remains tremendous reason for excitement. Our growing understanding of the biology involved in the inflammatory response, the factors that lead to safer small molecule kinase inhibitors, and the availability of selective tool molecules for interrogating specific nodes and pathways are all pushing the field forward. This article focuses on recent developments requiring novel approaches to create safe and effective small molecule kinase inhibitors and where further work is needed to realize the promise of small molecule kinase inhibitors for patient benefit.


Assuntos
Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Animais , Descoberta de Drogas , Humanos , Inibidores de Proteínas Quinases/uso terapêutico
8.
J Med Chem ; 60(14): 5955-5968, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28375009

RESUMO

With the development of ever-expanding synthetic methodologies, a medicinal chemist's toolkit continues to swell. However, with finite time and resources as well as a growing understanding of our field's environment impact, it is critical to refine what can be made to what should be made. This review seeks to highlight multiple cheminformatic approaches in drug discovery that can influence and triage design and execution impacting the likelihood of rapidly generating high-value molecules in a more sustainable manner. This strategy gives chemists the tools to design and refine vast libraries, stress "druglikeness", and rapidly identify SAR trends. Project success, i.e., identification of a clinical candidate, is then reached faster with fewer molecules with the farther-reaching ramification of using fewer resources and generating less waste, thereby helping "green" our field.


Assuntos
Química Farmacêutica/métodos , Descoberta de Drogas/métodos , Química Verde , Preparações Farmacêuticas/síntese química , Técnicas de Química Sintética , Simulação por Computador , Ensaios de Triagem em Larga Escala , Preparações Farmacêuticas/química , Relação Quantitativa Estrutura-Atividade
9.
J Med Chem ; 59(19): 9080-9093, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27564586

RESUMO

Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del746-750, T790M/L858R, and T790M/del746-750) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del746-750) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del746-750) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo and ADME-PK properties that are suitable for further evaluation. The reversible, noncovalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Modelos Moleculares , Mutação , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia
11.
ACS Med Chem Lett ; 7(1): 100-4, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819674

RESUMO

The rapid advancement of a series of noncovalent inhibitors of T790M mutants of EGFR is discussed. The optimization of pyridone 1, a nonselective high-throughput screening hit, to potent molecules with high levels of selectivity over wtEGFR and the broader kinome is described herein.

12.
Bioorg Med Chem Lett ; 26(2): 534-539, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26639762

RESUMO

The treatment of epidermal growth factor receptor (EGFR)-driven non-small cell lung cancers with the T790M resistance mutation remains a significant unmet medical need. We report the identification of 4-aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of EGFR, with excellent activity against the T790M resistance double mutants and initial single activating mutants. Using an optimization strategy focused on structure-based design and improving PK properties through metabolite identification, we obtained advanced leads with high oral exposure.


Assuntos
Receptores ErbB/antagonistas & inibidores , Furanos/farmacologia , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Sítios de Ligação , Cristalografia por Raios X , Cães , Receptores ErbB/química , Cloridrato de Erlotinib/farmacologia , Furanos/síntese química , Furanos/química , Furanos/farmacocinética , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Ligação de Hidrogênio , Indazóis/síntese química , Indazóis/química , Indazóis/farmacocinética , Camundongos , Microssomos Hepáticos/metabolismo , Mutação Puntual , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos
13.
J Med Chem ; 58(22): 8877-95, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26455919

RESUMO

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Genes erbB-1/efeitos dos fármacos , Animais , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Cães , Desenho de Fármacos , Técnicas de Silenciamento de Genes , Humanos , Técnicas In Vitro , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Mutação , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Med Chem ; 57(23): 9796-810, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25389560

RESUMO

The optimization of a series of aminooxazoline xanthene inhibitors of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aß lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aß reduction in a rat pharmacodynamic model (78% Aß reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Oxazolona/análogos & derivados , Inibidores de Proteases/síntese química , Xantenos/síntese química , Animais , Cristalografia por Raios X , Células HEK293 , Humanos , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/metabolismo , Oxazolona/síntese química , Oxazolona/farmacologia , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantenos/farmacologia
15.
J Med Chem ; 57(23): 10176-91, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25383627

RESUMO

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.


Assuntos
Aminopiridinas/síntese química , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Substituição de Aminoácidos , Aminopiridinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cristalografia por Raios X , Receptores ErbB/genética , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Metionina/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Treonina/genética
16.
J Med Chem ; 57(2): 309-24, 2014 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-24405172

RESUMO

Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.


Assuntos
Proteínas de Transporte/metabolismo , Glucoquinase/metabolismo , Hipoglicemiantes/química , Piperazinas/química , Animais , Sítios de Ligação , Proteínas de Transporte/química , Cristalografia por Raios X , Glucoquinase/química , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Conformação Proteica , Transporte Proteico , Ratos , Ratos Zucker , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/efeitos adversos , Sulfonamidas/química , Sulfonamidas/farmacologia
17.
ACS Comb Sci ; 15(9): 503-11, 2013 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-23927004

RESUMO

A platform that incorporates computational library design, parallel solution-phase synthesis, continuous flow hydrogenation, and automated high throughput purification and reformatting technologies was applied to the production of a 120-member library of 1-aryl-4-aminopiperidine analogues for drug discovery screening. The application described herein demonstrates the advantages of computational library design coupled with a flexible, modular approach to library synthesis. The enabling technologies described can be readily adopted by the traditional medicinal chemist without extensive training and lengthy process development times.


Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Triagem em Larga Escala , Simulação de Dinâmica Molecular , Piperidinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Algoritmos , Animais , Linhagem Celular , Permeabilidade da Membrana Celular/fisiologia , Humanos , Microssomos/química , Microssomos/metabolismo , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Ratos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Solubilidade , Suínos
18.
J Med Chem ; 56(15): 6007-21, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23586692

RESUMO

The medicinal chemistry subgroup of the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.


Assuntos
Química Farmacêutica/tendências , Descoberta de Drogas/tendências , Engenharia Química/métodos , Engenharia Química/tendências , Química Farmacêutica/métodos , Descoberta de Drogas/métodos , Química Verde/métodos , Química Verde/tendências
19.
Bioorg Med Chem Lett ; 23(7): 2056-60, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23481650

RESUMO

Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series.


Assuntos
Compostos Aza/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Compostos Aza/síntese química , Compostos Aza/química , Proteínas de Ciclo Celular/metabolismo , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Relação Estrutura-Atividade
20.
J Med Chem ; 55(4): 1698-705, 2012 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-22263917

RESUMO

Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 0.174 µM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.


Assuntos
Amidas/síntese química , Antineoplásicos/síntese química , Piperidinas/síntese química , Pirimidinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Quinase do Linfoma Anaplásico , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Transferência Ressonante de Energia de Fluorescência , Ensaios de Triagem em Larga Escala , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Conformação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade
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