RESUMO
This short review aims at highlighting recent design strategies hinged on using seven-membered rings. Analyses of the different selected examples coupled with torsion profiles derived from the CCDC suggest some of these strategies could have broad applications.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura MolecularRESUMO
In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library.
RESUMO
Minor structural modifications-sometimes single atom changes-can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.
RESUMO
This short review focuses on three aspects of rational drug design that we consider of utmost importance: the conformation of small molecules in solid form, the conformation of small molecules in solution and lesser studied interactions in protein-ligand complexes. Using examples from recent literature, we will illustrate these different aspects and how they have contributed to the discovery of potent modulators.
Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/química , Compostos Heterocíclicos/química , Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Ligação ProteicaRESUMO
Retinoids have a dominant role in topical acne therapy and to date, only RARß and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.
Assuntos
Acne Vulgar/tratamento farmacológico , Desenho de Fármacos , Receptores do Ácido Retinoico/agonistas , Retinoides/farmacologia , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Retinoides/síntese química , Retinoides/química , Relação Estrutura-Atividade , Receptor gama de Ácido RetinoicoRESUMO
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Desenho de Fármacos , Piridinas/farmacocinética , Quinolinas/farmacocinética , Quinolonas/farmacologia , Quinolonas/farmacocinética , Administração Oral , Proteínas Mutadas de Ataxia Telangiectasia/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Disponibilidade Biológica , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases , Piridinas/administração & dosagem , Piridinas/química , Quinolinas/administração & dosagem , Quinolinas/química , Quinolonas/administração & dosagem , Quinolonas/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Phototoxicity occurs when UV irradiation causes otherwise benign compounds to become irritant, sensitizers, or even genotoxic. This toxicity is particularly a concern after topical application and in dermatological programs where skin irritation can be incompatible with the desired therapeutic outcome. This brief article establishes that the intrinsic property forecast index (iPFI) can be used to evaluate the probability of a compound being phototoxic and gives medicinal chemists a practical tool to handle this liability.
Assuntos
Algoritmos , Química Farmacêutica/métodos , Dermatite Fototóxica , Heurística , Células 3T3 , Animais , Elétrons , Previsões , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Camundongos , Fármacos Fotossensibilizantes , Relação Estrutura-Atividade , Raios UltravioletaRESUMO
Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.
Assuntos
Iminas/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Sulfonamidas/farmacologia , Sulfóxidos/farmacologia , Animais , Agonismo Inverso de Drogas , Feminino , Humanos , Iminas/síntese química , Iminas/química , Ligantes , Camundongos Endogâmicos BALB C , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfóxidos/síntese química , Sulfóxidos/químicaRESUMO
With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with inâ vivo activity in an IL-23-induced mouse skin inflammation model.
Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Psoríase/tratamento farmacológico , Sulfonamidas/química , Administração Tópica , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Humanos , Concentração Inibidora 50 , Interleucina-17/metabolismo , Interleucina-23/farmacologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Psoríase/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Células Th17/citologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismoRESUMO
Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.
Assuntos
Proteína ADAM17/antagonistas & inibidores , Inibidores Enzimáticos/química , Proteína ADAM17/metabolismo , Administração Tópica , Animais , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Ácidos Hidroxâmicos/química , Camundongos , Camundongos Pelados , Microssomos Hepáticos/metabolismo , Oxazolona/toxicidade , Psoríase/tratamento farmacológico , Psoríase/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/prevenção & controle , Dermatopatias/veterinária , Solubilidade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kß and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50mg/kg twice daily orally) in the MCF7 xenograft model in mice.
Assuntos
Descoberta de Drogas , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Classe I de Fosfatidilinositol 3-Quinases , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Relação Estrutura-AtividadeRESUMO
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
Assuntos
Proteína ADAM17/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/química , Proteína ADAM17/metabolismo , Administração Tópica , Humanos , Psoríase/tratamento farmacológico , Psoríase/enzimologiaRESUMO
Targeting the IL17 pathway and more specifically the nuclear receptor RORγ is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORγ inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models.
Assuntos
Indazóis/química , Indazóis/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Agonismo Inverso de Drogas , Humanos , Simulação de Acoplamento Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Relação Estrutura-AtividadeRESUMO
Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.
Assuntos
Antineoplásicos/química , Compostos Heterocíclicos com 2 Anéis/química , Proteínas Nucleares/antagonistas & inibidores , Piperazinas/química , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Células CACO-2 , Proteínas de Ciclo Celular , Cristalografia por Raios X , Cães , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Xenoenxertos , Humanos , Camundongos SCID , Transplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacologia , Conformação Proteica , Pirazóis , Piridazinas , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.
Assuntos
Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Quinolinas/administração & dosagem , Quinolinas/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kß and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.
Assuntos
Antineoplásicos/farmacologia , Oxidiazóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cães , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Piperidinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Starting from compound 1, a potent PI3Kα inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3Kα and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Kα, with excellent kinase selectivity.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Sequência de Aminoácidos , Sítios de Ligação , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Modelos Moleculares , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/química , Proteínas Mutantes/genética , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/genética , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologiaRESUMO
Novel 2,3-diarylindoles bearing an amine substituent at the indole 5- and 6-positions have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 27.
Assuntos
Coccidiostáticos/síntese química , Indóis/síntese química , Animais , Coccidiose/tratamento farmacológico , Coccidiose/enzimologia , Coccidiose/parasitologia , Coccidiostáticos/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria tenella/efeitos dos fármacos , Eimeria tenella/enzimologia , Eimeria tenella/crescimento & desenvolvimento , Indóis/farmacologia , Aves Domésticas/parasitologia , Piridinas/síntese químicaRESUMO
Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.