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
Herein we describe our efforts using a late stage functionalization together with more traditional synthetic approaches to generate fluorinated analogues of the clinical candidate AZD9833. The effects of the addition of fluorine on the lipophilicity, permeability, and metabolism are discussed. Many of these changes were tolerated in terms of pharmacology and resulted in high quality molecules which reached advanced stages of profiling in the testing cascade.
RESUMO
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
We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.
Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Pirróis/química , Tiazinas/química , Animais , Sítios de Ligação , Células CACO-2 , Cães , Desenho de Fármacos , Meia-Vida , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Simulação de Dinâmica Molecular , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Permeabilidade/efeitos dos fármacos , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazinas/farmacocinética , Tiazinas/farmacologiaRESUMO
A palladium mediated C-H aziridination reaction of 3,3,5,5-substituted-piperazin-2-ones has been developed using phenyliodonium diacetate (PIDA) and succinic acid to give synthetically useful bicyclic aziridines, in moderate to good yields. Succinic acid was found to be key for selectively promoting C-N bond formation (aziridination) and suppressing competitive acetoxylation. Analysis of the reaction kinetics revealed the role of succinic acid in promoting an equilibrium between monomeric and dimeric palladium species in the rate determining step of the reaction. The aziridines can be ring-opened by nucleophiles under Lewis or Brønsted acidic conditions to give formal C-H functionalized products. The reaction conditions can be further manipulated to produce acetoxylated, diacetoxylated and even triacetoxylated materials through the use of acetic acid and increased oxidant stoichiometry.
RESUMO
Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Linhagem Celular Tumoral , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Modelos Moleculares , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de AcetilRESUMO
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
Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro, p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Piridonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Desenho de Fármacos , Sinergismo Farmacológico , Feminino , Humanos , Irinotecano , Camundongos , Camundongos Nus , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.
Assuntos
Agonismo Inverso de Drogas , Receptores de Grelina/agonistas , Receptores de Grelina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Receptores de Grelina/metabolismo , Relação Estrutura-Atividade , Ureia/químicaRESUMO
The development of a stereoselective total synthesis of ß-dihydroagarofuran 4 is described. This compound contains the same oxygenation pattern on its 'lower-rim' as found in the natural sesquiterpene (-)-euonyminol (1) and it is expected that the route described should be applicable to the synthesis of that complex natural product. (-)-Euonyminol is found as the core scaffold of a series of complex macrodilactone sesquiterpenoids isolated from the Celastraceae which possess interesting biological activities (e.g. anti-HIV activity). The synthetic route builds upon an epoxidative asymmetric desymmetrisation of meso-diallylic alcohol 10 that we have reported previously. It features a lactate Ireland-Claisen rearrangement to establish the quaternary stereocentre at C11 (27â28a) and an unusual dealkylative intramolecular epoxide-opening by the C11 methyl ether to establish the tetrahydrofuranyl C-ring of the ß-dihydroagarofuran skeleton (35â36).
Assuntos
Modelos Químicos , Sesquiterpenos/química , Sesquiterpenos/síntese química , Técnicas de Química Sintética , Furanos/química , Oxigênio/química , Propanóis/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
The synthesis of a range of novel ynone trifluoroborates has been achieved, in a two-pot process from propargylic alcohols. These alkynes have been subsequently used in the formation of a range of pyrazole trifluoroborate salts via cyclization with hydrazines. The products are generated with high levels of regiocontrol and in excellent yields and represent versatile synthetic intermediates.
Assuntos
Pirazóis/síntese química , Ciclização , Estrutura MolecularRESUMO
Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
Assuntos
Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pirimidinas/química , Pirróis/química , Água/química , Administração Oral , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Proteínas de Choque Térmico HSP90/metabolismo , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Relação Estrutura-AtividadeRESUMO
The first synthesis of hydroxy-iso-evoninic acid (2), a pyridyl diacid found as a macrodilactone bridging ligand in bioactive Celastraceae sesquiterpenoid-based natural products, has been achieved in 9 steps and an overall yield of 26%. The synthesis utilizes a benzilic ester rearrangement (BER) and a late stage benzylic oxidation to give access to all four stereoisomers whose absolute stereochemistry was assigned following chromatographic separation and anomalous dispersion X-ray crystallography.
Assuntos
Propionatos/síntese química , Piridinas/síntese química , Hidroxilação , Modelos Moleculares , Estrutura Molecular , OxirreduçãoRESUMO
An evaluation of the Bruker SMART X2S for the collection of crystallographic diffraction data, structure solution and refinement is carried out with a variety of materials with different electron densities, presenting some of the successes and challenges of automation in chemical crystallography.