RESUMO
We report the synthesis and biological evaluation of 5-substituted indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing heterocycle forming and multicomponent reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for Gsk3ß, Rock2, and Egfr.
Assuntos
Desenho de Fármacos , Compostos Heterocíclicos/química , Indazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Indazóis/química , Indazóis/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
We report the synthesis and biological evaluation of 5-substituted indazoles and amino indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing [2+3] cycloaddition reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for numerous kinases such as Rock2, Gsk3ß, Aurora2 and Jak2.
Assuntos
Desenho de Fármacos , Indazóis , Inibidores de Proteínas Quinases , Ciclização , Indazóis/síntese química , Indazóis/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Flow chemistry has gained considerable recognition as a simple, efficient, and safe technology for the synthesis of many types of organic and inorganic molecules ranging in scope from large complex natural products to silicon nanoparticles. In this paper we describe a method that adapts flow chemistry to the synthesis of libraries of compounds using a fluorous immiscible solvent as a spacer between reactions. The methodology was validated in the synthesis of two small heterocycle containing libraries. The reactions were performed on a 0.2 mmol scale, enabling tens of milligrams of material to be generated in a single 200 mL reaction plug. The methodology allowed library synthesis in half the time of conventional microwave synthesis while maintaining similar yields. The ability to perform multiple, potentially unrelated reactions in a single run is ideal for making small quantities of many different compounds quickly and efficiently.
Assuntos
Química Orgânica/métodos , Técnicas de Química Combinatória/métodos , Bibliotecas de Moléculas Pequenas/síntese química , Química Orgânica/instrumentação , Técnicas de Química Combinatória/instrumentação , Micro-Ondas , Estrutura Molecular , Solventes/químicaRESUMO
This review describes recent advances in the application of isocyanide-based multicomponent reactions (IMCRs) in drug discovery and summarizes the various chemotypes used to probe biological targets. In the past couple of years, IMCR-derived ligands have been used to develop agents against infectious diseases and to interfere with protein-protein interactions. Additionally, they were active against a variety of targets such as enzymes, GPCRs and ion channels. The rational for the chemical biologist to apply such diversity generating chemistries is also discussed.
Assuntos
Cianetos/química , Cianetos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Ligação Proteica/efeitos dos fármacosRESUMO
We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively).
Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Células 3T3 , Animais , Azepinas/química , Ligação de Hidrogênio , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure-activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7 S,8 R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7 S,8 R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED50 of 0.8 mg/kg. All these results suggest (7 S,8 R)-27a and 51b as new GlyT1 inhibitors worthy of further profiling.
Assuntos
Encéfalo/efeitos dos fármacos , Cromanos/química , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Tetra-Hidronaftalenos/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Ligação Competitiva , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Pirrolidinonas/efeitos adversos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , XenopusRESUMO
The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders associated with hypofunction of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. Herein, we describe the synthesis and biological evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chemical structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compounds derived from iterative structure-activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclinical pharmacokinetics, and manageable DDI and bioactivation liabilities.
Assuntos
Encéfalo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Pirrolidinas/química , Sulfonamidas/química , Animais , Encéfalo/metabolismo , Técnicas de Química Sintética , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos , Microssomos Hepáticos/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Pirrolidinonas/efeitos adversos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , XenopusRESUMO
The design and synthesis of quality compound libraries is of critical importance to any pharmaceutical company that relies on high throughput screening efforts for the identification of lead compounds. In this perspective, we use a moment of inertia derived shape analysis to interrogate potential libraries for chemical synthesis. An analysis of known 'Rule of Five' compliant drug shapes using this methodology clearly highlights compound libraries that may be reasonably expected, shape wise, to interact with biologically relevant protein active site topography and those that, although being structurally diverse in shape, have little chance of being pharmacologically productive. The use of multicomponent reactions as a means of producing structurally novel, bioactive compounds in a synthetically expeditious manner is also highlighted.
Assuntos
Química Farmacêutica , Desenho de Fármacos , Conformação MolecularRESUMO
The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.
Assuntos
Alcinos/síntese química , Antineoplásicos/síntese química , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Indenos/síntese química , Pirazóis/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tiofenos/síntese química , Alcinos/efeitos adversos , Alcinos/farmacologia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Ligação Competitiva , Linhagem Celular , Canal de Potássio ERG1 , Edema/induzido quimicamente , Edema/tratamento farmacológico , Estradiol , Canais de Potássio Éter-A-Go-Go/fisiologia , Feminino , Humanos , Indenos/efeitos adversos , Indenos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Técnicas de Patch-Clamp , Ligação Proteica , Pirazóis/efeitos adversos , Pirazóis/metabolismo , Pirazóis/farmacologia , Ensaio Radioligante , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/metabolismo , Tiofenos/farmacologia , Doenças Uterinas/induzido quimicamente , Doenças Uterinas/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
[structure: see text]. We report a new methodology for the construction of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by combining the Ugi multicomponent reaction with [2+2] enone-olefin photochemical transformations. The overall sequence is capable of creating up to five stereocenters; however, in most cases, only two diastereomers are observed.
RESUMO
Herein we report a concise protocol for the diastereoselective synthesis of novel bridged bicyclic lactams from commercially available components by the sequence of Ugi, ring-closing metathesis (RCM), and Heck reactions. X-ray diffraction studies revealed that the bicyclic products contain varying degrees of pyramidalization of the bridgehead nitrogen atom.
Assuntos
Lactamas/síntese química , Cristalografia por Raios X , Ciclização , Lactamas/química , Modelos Moleculares , Estrutura Molecular , EstereoisomerismoRESUMO
In recent years there has been great interest in developing protein kinase inhibitors as therapeutic agents for a variety of diseases. This article provides an overview on the history, development and validity of kinases as drug targets, as well as a description of kinase research, including its limitations, challenges and successes.
Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/isolamento & purificação , Domínio Catalítico , Diabetes Mellitus/tratamento farmacológico , História do Século XX , História do Século XXI , Humanos , Inflamação/tratamento farmacológico , Estrutura Molecular , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/história , Proteínas Quinases/químicaRESUMO
The lipoxins (LX) are a class of potent endogenous oxygenated products that are enzymatically generated from arachidonic acid and have novel anti-inflammatory properties and promote resolution. Elucidation of the biochemical pathways involved in the metabolic inactivation of LX and the discovery of the aspirin-triggered lipoxins (ATL) provided the basis for the design and synthesis of stable analogs of LX and ATL. This special issue review describes the efforts that led to the design and synthesis of stable LX/ATL mimetics, which permitted the detailed elucidation of their novel biological roles, leading to the development of new anti-inflammatory agents that mimic their actions. These synthetic molecules provided the means to uncover the physiologic roles of both the LX and the ATL biosynthetic pathways which led to several unexpected discoveries. Among these findings is the involvement of polyisoprenyl phosphates (PIPP) in intracellular signaling mediated by presqualene diphosphate (PSDP), and the recognition of the novel roles of these lipid mediators in regulating cell trafficking during inflammation as well as in promoting resolution of inflammatory processes. These efforts also provided the basis for examining the potential therapeutic role of LX/ATL stable mimetics and led to the development of new analogs with improved pharmacokinetics that opened the way to potentially new approaches to treating human diseases.
Assuntos
Desenho de Fármacos , Inflamação/fisiopatologia , Lipoxinas/síntese química , Anti-Inflamatórios/farmacologia , Aspirina/farmacologia , Eicosanoides/biossíntese , Humanos , Lipoxinas/metabolismo , Lipoxinas/uso terapêutico , Estrutura MolecularRESUMO
IMPORTANCE OF THE FIELD: As an integral part of lead generation and optimization, scaffold discovery has broad implications in drug discovery. Currently available chemical scaffolds might be inadequate to provide drug-like ligands for new targets such as phosphatases and protein-protein interactions and therapeutically useful chemical space needs to be continuously explored. New scaffolds are often desired to overcome major hurdles (e.g., potency plateau, selectivity, pharmacokinetics, etc.) in lead generation and optimization. Timely discovery of proof-of-concept compounds facilitates target validation, diversifies clinical candidates and improves the overall success rate of drug discovery. AREAS COVERED IN THIS REVIEW: This analysis discusses the strategies involved in finding new scaffolds (i.e., fragment-, ligand- and structure-based design) and their applications (e.g., improve potency/selectivity, multiple ligand design, protein-protein interactions, etc.) in drug discovery. WHAT THE READER WILL GAIN: The readers will learn the strategies involved in scaffold design and the problems that they solve. They will also gain the understanding of the circumstances suitable for using scaffold design. TAKE HOME MESSAGE: Scaffold is defined by the authors as a biological target dependent concept. Therapeutically useful scaffolds are limited and the identification of new scaffolds is sometimes required to overcome major optimization hurdles. However, depending on the promiscuity of the binding pocket of the target and the validity of the optimization protocol, finding better scaffolds can be a challenging task. Several strategies in scaffold discovery have emerged or matured owing to recent trends such as pursuit of targets from new proteomic families, lack of validated targets, advances in synthesis and biological assays and adoption of in vitro activity-driven screening paradigms.
RESUMO
Protein kinases continue to hold tremendous promise for therapeutic intervention, and the search for novel, safe and efficacious kinase inhibitors has intensified over the past decade. Given that most kinases are readily inhibited by organic small molecules and that a wealth of structural data exists on kinase-inhibitor complexes, there has been almost universal success in the design and identification of potent kinase inhibitors. The issues of non-selectivity and congested IP space, however, present formidable challenges for the successful clinical development of these compounds. We describe a systematic approach implemented at Abbott to enable the rapid discovery and design of novel and potent kinase inhibitors that provide additional opportunities for targeting new intellectual property space and achieving acceptable selectivity profiles.
Assuntos
Sistemas de Liberação de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/efeitos dos fármacos , Desenho de Fármacos , Humanos , Propriedade Intelectual , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/metabolismo , Bibliotecas de Moléculas PequenasRESUMO
We report the synthesis and biological evaluation of 5-substituted 1,4-dihydroindeno[1,2-c]pyrazoles as multitargeted kinase inhibitors. Initial efforts focused on the development of selective KDR inhibitors, while later strategies involved the improvement of potency toward multiple kinase targets. Thus, several compounds were identified as potent KDR, Flt1, Flt3, and c-Kit inhibitors.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Pirazóis/síntese químicaRESUMO
To aid in the identification of novel melanin-concentrating hormone receptor 1 (MCHr1) antagonists, a unique virtual library of readily synthesized molecules was designed and assembled based on 323 monomer compounds containing reactive moieties in combination with 30 core molecules having diamine functionality. The resulting library of 3,129,870 molecules was searched using three-dimensional shape similarity measures that were complimented with a novel electrostatic distribution similarity-matching algorithm. One of the top scoring hits in this library was synthesized and characterized for MCHr1 antagonism, where it exhibited at least a threefold improvement in binding affinity and cellular potency relative to the parent MCHr1 ligand. This work demonstrates that the use of shape and electrostatic similarity matching in combination with a well-designed virtual library can be used to augment standard medicinal chemistry techniques.
Assuntos
Algoritmos , Simulação por Computador , Modelos Moleculares , Receptores de Somatostatina/antagonistas & inibidores , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Estrutura Molecular , Receptores de Somatostatina/química , Eletricidade EstáticaRESUMO
We report the synthesis of kinase targeted libraries based on the thienopyrazole scaffold. Several thienopyrazole analogs have been identified as submicromolar inhibitors of KDR.
Assuntos
Química Farmacêutica/métodos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Fosfotransferases/química , Pirazóis/química , Pirazóis/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Modelos QuímicosRESUMO
A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.
Assuntos
Indenos/farmacologia , Pirazóis/farmacologia , Administração Oral , Animais , Química Farmacêutica , Desenho de Fármacos , Edema/patologia , Estradiol/farmacologia , Feminino , Indenos/química , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Modelos Moleculares , Pirazóis/química , Relação Estrutura-Atividade , Útero/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/químicaRESUMO
A series of 1,4-dihydroindeno[1,2-c]pyrazoles with a 3-thiophene substituent carrying a urea-type side chain were identified as potent multitargeted (VEGFR and PDGFR families) receptor tyrosine kinase inhibitors. A KDR homology model suggested that the urea moiety is able to interact with a recognition motif in the hydrophobic specificity pocket of the enzyme.