RESUMO
The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
Assuntos
Antineoplásicos/metabolismo , Cinamatos/química , Cinamatos/metabolismo , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/síntese química , Moduladores de Receptor Estrogênico/farmacologia , Indóis/química , Indóis/metabolismo , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos Fase I como Assunto , Regulação para Baixo/efeitos dos fármacos , Desenho de Fármacos , Feminino , Humanos , Injeções Intramusculares , Difração de Raios XRESUMO
High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.
Assuntos
Descoberta de Drogas , Hepatócitos/efeitos dos fármacos , Complexos Multiproteicos/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tioureia/análogos & derivados , Células Cultivadas , Hepatócitos/citologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tioureia/química , Tioureia/farmacologiaRESUMO
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/genética , Técnicas de Química Sintética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Feminino , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos Endogâmicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A rhodium(I) catalyst incorporating the Me-DuPhos ligand promotes enantioselective intermolecular hydroacylation between beta-S-aldehydes and 1,3-disubstituted allenes. The nonconjugated enone products are obtained in good yields and with high enantioselectivities.
Assuntos
Aldeídos/química , Alcenos/química , Química/métodos , Ródio/química , Carbono/química , Catálise , Ligantes , Metais/química , Modelos Químicos , Estrutura Molecular , Estereoisomerismo , TemperaturaRESUMO
The use of beta-S-substituted aldehydes in rhodium-catalyzed intermolecular hydroacylation reactions is reported. Aldehydes substituted with either sulfide or thioacetal groups undergo efficient hydroacylation with a variety of electron-poor alkenes, such as enoates, in Stetter-like processes and with both electron-poor and neutral alkynes. In general, the reactions with electron-poor alkenes demonstrate good selectivity for the linear regioisomer, and the reactions with alkynes provide enone products with excellent selectivity for the E-isomers. The scope of the process was shown to be broad, tolerating a variety of substitution patterns and functional groups on both reaction components. A novel CN-directing effect was shown to be responsible for reversing the regioselectivity in a number of alkyne hydroacylation reactions. Catalyst loadings as low as 0.1 mol % were achievable.
Assuntos
Aldeídos/química , Alcenos/química , Alcinos/química , Cetonas/síntese química , Ródio/química , Catálise , Cetonas/química , Estrutura Molecular , EstereoisomerismoRESUMO
[reaction: see text]. Beta-thioacetal-substituted aldehydes, which are conveniently prepared from the corresponding ynals, can be combined with a range of alkynes or electron-poor alkenes to deliver intermolecular hydroacylation adducts. The reactions employ [Rh(dppe)]ClO4 as a catalyst and are proposed to proceed via a chelated rhodium acyl intermediate. The thioacetal-containing products can be deprotected to the corresponding ketones or reduced to alkanes in good yields.
RESUMO
The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented.