RESUMO
The isothiourea-catalyzed enantioselective 1,6-conjugate addition of para-nitrophenyl esters to 2,6-disubstituted para-quinone methides is reported. para-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the para-nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of para-nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides at up to 99% yield. Although low diastereocontrol is observed, the diastereoisomeric ester products are separable and formed with high enantiocontrol (up to 94:6 er).
RESUMO
The highly enantioselective alkylation of α-CF3 enolates, generated from triketopiperazines, has been accomplished through use of a bifunctional thiourea organocatalyst to facilitate 1,4-addition to varied enone acceptors. On treatment with appropriate nitrogen nucleophiles, the chiral triketopiperazine products undergo a metamorphosis, to provide novel fused heterocyclic lactams such as extended pyrazolopyrimidines.
RESUMO
Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.
Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Camundongos , Humanos , Animais , Feminino , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Linhagem CelularRESUMO
A comprehensive study of the enantioselective Pd-catalyzed α-arylation of N-Boc pyrrolidine has been carried out. The protocol involves deprotonation of N-Boc pyrrolidine using s-BuLi/(-)-sparteine in TBME or Et(2)O at -78 °C, transmetalation with ZnCl(2) and Negishi coupling using Pd(OAc)(2), t-Bu(3)P-HBF(4) and the aryl bromide. This paper reports several new features including in situ React IR spectroscopic monitoring of the process; use of (-)-sparteine and the (+)-sparteine surrogate to access products with opposite configuration; development of a catalytic asymmetric lithiation-Negishi coupling reaction; extension to a wide range of heteroaromatic bromides; total synthesis of (R)-crispine A, (S)-nicotine and (S)-SIB-1508Y via short synthetic routes; and examples of α-vinylation of N-Boc pyrrolidine using vinyl bromides exemplified by the total synthesis of naturally occurring (+)-maackiamine (thus establishing its configuration as (R)). In this way, the full scope and limitations of the methodology are delineated.
Assuntos
Isoquinolinas/síntese química , Paládio/química , Piridinas/química , Pirrolidinas/química , Catálise , Isoquinolinas/química , Estrutura Molecular , Esparteína/química , Análise Espectral , EstereoisomerismoRESUMO
Optimization of a series of azabenzimidazoles identified from screening hit 2 and the information gained from a co-crystal structure of the azabenzimidazole-based lead 6 bound to CDK9 led to the discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles 38 and 39. These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 in vivo.
Assuntos
Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Descoberta de Drogas , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinase 9 Dependente de Ciclina/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 , Relação Estrutura-AtividadeRESUMO
The high yielding asymmetric deprotonation trapping of N-Boc piperidine is successfully realized using s-BuLi and a (+)-sparteine surrogate. Monitoring of the lithiation by in situ React IR allowed the direct observation of a prelithiation complex.
Assuntos
Piperidinas/química , Prótons , Espectrofotometria Infravermelho , EstereoisomerismoRESUMO
A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
Assuntos
Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridinas/química , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Quinase 9 Dependente de Ciclina/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Solubilidade , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.
Assuntos
Antineoplásicos/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Administração Oral , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ciclização , Descoberta de Drogas , Feminino , Humanos , Lipídeos/química , Estrutura Molecular , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Relação Estrutura-AtividadeRESUMO
Organocatalysed asymmetric Michael additions of substituted triketopiperazines to enones afford products in high yield and enantiomeric ratio (er). Further modification delivers products possessing natural product (NP) scaffolds including diazabicyclo[2.2.1]heptane, prolinamide and harmicine.
RESUMO
The s-BuLi complex of a cyclohexane-derived diamine is as efficient as s-BuLi/(-)-sparteine for the asymmetric deprotonation of N-Boc pyrrolidine. This is the first example of high enantioselectivity using a non-sparteine-like diamine in such reactions. The (S,S)-diamine is a useful (+)-sparteine surrogate and was utilized in short syntheses of (-)-indolizidine 167B and an intermediate for the synthesis of the CCK antagonist (+)-RP 66803.
Assuntos
Diaminas/química , Indolizinas/síntese química , Pirrolidinas/química , Esparteína/química , Colecistocinina/antagonistas & inibidores , Diaminas/síntese química , Indolizinas/química , Prolina/análogos & derivados , Prolina/síntese química , Prolina/farmacologia , EstereoisomerismoRESUMO
While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.
Assuntos
Descoberta de Drogas , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Proteínas Mutantes/antagonistas & inibidores , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Quinazolinas/química , Quinazolinas/farmacologia , Triazóis/química , Triazóis/farmacologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Humanos , Modelos Moleculares , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Quinazolinas/farmacocinética , Distribuição Tecidual , Triazóis/farmacocinética , Células Tumorais CultivadasRESUMO
[reaction: see text] (+/-)-Cytisine has been synthesized in 19% overall yield via a six-step approach from commercially available materials. Key features of this new strategy are as follows: (i) initial construction of the bispidine core, (ii) lithiation-transmetalation-allylation of an N-Boc-bispidine, and (iii) a Pd/C-mediated dihydropyridone oxidation-N-debenzylation process.
Assuntos
Alcaloides/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Lítio/química , Alcaloides/química , Azocinas/síntese química , Azocinas/química , Modelos Moleculares , Estrutura Molecular , Quinolizinas/síntese química , Quinolizinas/químicaRESUMO
In ongoing studies towards novel hepatitisâ C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.
Assuntos
Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cães , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral , Hepacivirus/metabolismo , Humanos , Ligação de Hidrogênio , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
A series of sarcosine based indandione hGlyT1 inhibitors has been developed. Optimization of substitution around the indandione and sarcosine moieties has led to highly potent inhibitors at hGlyT1, which show selectivity over a number of other receptors.