RESUMO
ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps.
Assuntos
Antineoplásicos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Antineoplásicos/farmacologia , Hidrogenação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidoresRESUMO
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Citocinas/química , Citocinas/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Isoindóis/química , Isoindóis/farmacocinética , Isoindóis/farmacologia , Isoindóis/uso terapêutico , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Nicotinamida Fosforribosiltransferase/química , Nicotinamida Fosforribosiltransferase/metabolismo , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tiazóis/farmacologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/síntese química , Piperazinas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Adamantano/farmacocinética , Animais , Linhagem Celular , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Piperazinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236-45. ©2017 AACR.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Trifosfato de Adenosina/genética , Trifosfato de Adenosina/metabolismo , Animais , Sinalização do Cálcio/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Citocinas/genética , Reparo do DNA/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Camundongos , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.
Assuntos
Benzilaminas/síntese química , Hipoglicemiantes/síntese química , Receptores de Glucocorticoides/antagonistas & inibidores , Sulfonamidas/síntese química , Fosfatase Alcalina/biossíntese , Fosfatase Alcalina/genética , Animais , Benzilaminas/efeitos adversos , Benzilaminas/farmacologia , Células Cultivadas , Cricetinae , Cricetulus , Dexametasona/farmacologia , Feminino , Genes Reporter , Glucocorticoides/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Camundongos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Gravidez , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Ativação Transcricional/efeitos dos fármacos , Tirosina Transaminase/biossíntese , Útero/efeitos dos fármacosRESUMO
Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/síntese química , Adamantano/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Tecido Adiposo/enzimologia , Animais , Encéfalo/enzimologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Humanos , Indicadores e Reagentes , Fígado/enzimologia , Camundongos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
High throughput screening efforts have identified a novel class of dichloroaniline amide 11beta-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Carbenoxolona/química , Carbenoxolona/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Conformação Molecular , Piperazinas/química , Piperazinas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
A series of potent and selective adamantane aminoamide 11-beta-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure-activity relationship studies resulted in the discovery of dual human and mouse 11-beta-HSD-1 potent and selective inhibitors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/síntese química , Adamantano/farmacologia , Cianetos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A new class of selective nonsteroidal glucocorticoid receptor modulators typified by N-[3-[benzyl-(4-chloro-2-fluoro-benzyl)-amino]-2-methyl-phenyl]-methanesulfonamide 19 has been discovered.
Assuntos
Receptores de Glucocorticoides/efeitos dos fármacos , Animais , Compostos de Benzil , Humanos , Ratos , Relação Estrutura-Atividade , SulfonamidasRESUMO
Bile acid conjugates of a selective nonsteroidal glucocorticoid receptor modulator were prepared and evaluated. Potent GR binding conjugates that showed improved metabolic stability were discovered. However, cellular potency and pharmacokinetics were not substantially improved.
Assuntos
Ácidos e Sais Biliares/química , Receptores de Glucocorticoides/efeitos dos fármacos , Animais , Ácidos e Sais Biliares/farmacocinética , Disponibilidade Biológica , Ratos , Ratos Sprague-DawleyRESUMO
A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.
Assuntos
Sistemas de Liberação de Medicamentos , Glucuronídeos/metabolismo , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/farmacologia , Fígado/efeitos dos fármacos , Mifepristona/administração & dosagem , Mifepristona/farmacologia , Receptores de Glucocorticoides/antagonistas & inibidores , Administração Oral , Fosfatase Alcalina/antagonistas & inibidores , Animais , Ligação Competitiva/efeitos dos fármacos , Dexametasona/farmacocinética , Circulação Êntero-Hepática , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucocorticoides/farmacocinética , Glucuronídeos/farmacocinética , Antagonistas de Hormônios/farmacocinética , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Injeções Intravenosas , Microssomos Hepáticos/metabolismo , Mifepristona/farmacocinética , Compostos de Amônio Quaternário , Ratos , Ratos Sprague-Dawley , Tirosina Transaminase/antagonistas & inibidoresRESUMO
The optimization of a series of nonsteroidal glucocorticoid modulators is reported. Potent selective GR ligands that have improved metabolic stability were discovered typified by the subnanomolar acid 12 (GR binding IC(50)=0.6 nM).
Assuntos
Receptores de Glucocorticoides/efeitos dos fármacos , Humanos , Ligantes , Ligação Proteica , Receptores de Glucocorticoides/metabolismoRESUMO
Biaryl amides derived from a reported series of ureas 1 were evaluated and found to be potent human glucagon receptor antagonists. The benzofuran analogue 6i was administered in Sprague-Dawley rats and blocked the effects of an exogenous glucagon challenge.
Assuntos
Amidas/farmacologia , Receptores de Glucagon/antagonistas & inibidores , Amidas/química , Animais , Haplorrinos , Humanos , Camundongos , Ratos , Ratos Sprague-DawleyRESUMO
The synthesis, activity, metabolic stability, and pharmacokinetics of steroidal and nonsteroidal glucocorticoid receptor modulator-statin hybrids is reported. Potent steroidal antagonist-statin hybrids like 22 (h-GR binding IC(50)=7 nM) and nonsteroidal modulator hybrids like 16 (h-GR binding IC(50)=2 nM) were discovered. Appending a 'statin'-like diol-acid group to the modulators dramatically improved metabolic stability (and in some cases hepatocyte activity), but did not impart hepatoselectivity.