RESUMO
Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.
Assuntos
Antineoplásicos/uso terapêutico , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Imidazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Cães , Células HCT116 , Haplorrinos , Histonas/metabolismo , Humanos , Imidazóis/administração & dosagem , Imidazóis/síntese química , Imidazóis/farmacocinética , Camundongos , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Estereoisomerismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Optimization of the ADME properties and pharmacokinetic (PK) profile of compounds is one of the critical activities in any medicinal chemistry campaign to discover a future clinical candidate. Finding ways to expedite the process to address ADME/PK shortcomings and reduce the number of compounds to synthesize is highly valuable. This article provides practical guidelines and a case study on the use of ML ADME models to guide compound design in small molecule lead optimization. These guidelines highlight that ML models cannot have an impact in a vacuum: they help advance a program when they have the trust of users, are tuned to the needs of the program, and are integrated into decision-making processes in a way that complements and augments the expertise of chemists.
RESUMO
The structure-activity relationships of new Aurora A/B kinase inhibitors derived from the previously identified kinase inhibitor 12 are described. Introduction of acetic acid amides onto the pyrazole of compound 12 was postulated to influence Aurora A/B selectivity and improve the profile against off-target kinases. The SAR of the acetic acid amides was explored and the effect of substitution on enzyme inhibition as well as mechanism-based cell activity was studied. Additionally, several of the more potent inhibitors were screened for their off-target kinase selectivity.
Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Aurora Quinases , Cristalografia por Raios X , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A series of substituted imidazo[1,2-a]pyrazin-8-amines were discovered as novel breast tumor kinase (Brk)/protein tyrosine kinase 6 (PTK6) inhibitors. Tool compounds with low-nanomolar Brk inhibition activity, high selectivity towards other kinases and desirable DMPK properties were achieved to enable the exploration of Brk as an oncology target.
Assuntos
Neoplasias da Mama/enzimologia , Imidazóis/síntese química , Imidazóis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazinas/síntese química , Pirazinas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Aurora Quinases , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Simulação por Computador , Proteínas de Ligação a DNA/metabolismo , Dasatinibe , Relação Dose-Resposta a Droga , Desenho de Fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Concentração Inibidora 50 , Melanócitos/fisiologia , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/genética , Oncogenes , Fenótipo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proto-Oncogenes , Pirazinas/química , Pirazinas/farmacocinética , Pirimidinas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Relação Estrutura-Atividade , Tiazóis/metabolismoRESUMO
Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.
Assuntos
Imidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/química , Animais , Aurora Quinase A , Aurora Quinases , Avaliação Pré-Clínica de Medicamentos , Imidazóis/síntese química , Imidazóis/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Pirazinas/síntese química , Pirazinas/farmacocinética , RatosRESUMO
The synthesis and structure-activity relationships (SAR) of novel, potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors are described. The X-ray crystal structure of imidazo[1,2-a]pyrazine Aurora inhibitor 1j is disclosed. Compound 10i was identified as lead compound with a promising overall profile.
Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Aurora Quinases , Proteínas Sanguíneas/metabolismo , Cristalografia por Raios X , Descoberta de Drogas , Citometria de Fluxo , Humanos , Imidazóis/química , Imidazóis/metabolismo , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Pirazinas/química , Pirazinas/metabolismo , Relação Estrutura-AtividadeRESUMO
We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.
Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Administração Oral , Animais , Aurora Quinases , Disponibilidade Biológica , Linhagem Celular Tumoral , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/química , Pirazinas/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Descoberta de Drogas , Inibidores de Proteases/química , Tartaratos/química , Fator de Necrose Tumoral alfa/metabolismo , Proteína ADAM17 , Sítios de Ligação , Técnicas de Química Combinatória , Cristalografia por Raios X , Descoberta de Drogas/métodos , Humanos , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Tartaratos/metabolismo , Tartaratos/farmacologiaRESUMO
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores de Proteases/química , Tartaratos/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Sítios de Ligação , Simulação por Computador , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Tartaratos/síntese química , Tartaratos/farmacocinéticaRESUMO
Complement factor D (FD), a highly specific S1 serine protease, plays a central role in the amplification of the alternative complement pathway (AP) of the innate immune system. Dysregulation of AP activity predisposes individuals to diverse disorders such as age-related macular degeneration, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and paroxysmal nocturnal hemoglobinuria. Previously, we have reported the screening efforts and identification of reversible benzylamine-based FD inhibitors (1 and 2) binding to the open active conformation of FD. In continuation of our drug discovery program, we designed compounds applying structure-based approaches to improve interactions with FD and gain selectivity against S1 serine proteases. We report herein the design, synthesis, and medicinal chemistry optimization of the benzylamine series culminating in the discovery of 12, an orally bioavailable and selective FD inhibitor. 12 demonstrated systemic suppression of AP activation in a lipopolysaccharide-induced AP activation model as well as local ocular suppression in intravitreal injection-induced AP activation model in mice expressing human FD.
Assuntos
Benzilaminas/farmacologia , Via Alternativa do Complemento/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Animais , Benzilaminas/síntese química , Benzilaminas/metabolismo , Sítios de Ligação , Fator D do Complemento/antagonistas & inibidores , Fator D do Complemento/química , Fator D do Complemento/metabolismo , Cães , Desenho de Fármacos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Conformação Proteica , Ratos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/metabolismoRESUMO
Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.
Assuntos
Ativadores de Enzimas/síntese química , Ativadores de Enzimas/uso terapêutico , Glaucoma/tratamento farmacológico , Guanilil Ciclase Solúvel/efeitos dos fármacos , Administração Oftálmica , Administração Tópica , Animais , Células CHO , Cricetinae , Cricetulus , GMP Cíclico/biossíntese , Descoberta de Drogas , Ativadores de Enzimas/administração & dosagem , Humanos , Pressão Intraocular/efeitos dos fármacos , Macaca fascicularis , Soluções Oftálmicas , Oxirredução , CoelhosRESUMO
The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC50 = 250 nM) and low solubility (5 µM). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.
RESUMO
The Rh(I) catalyzed intramolecular [4 + 2] cycloaddition of representative achiral and chiral enedienes has been shown to proceed with excellent levels of stereoselectivity and in high yield under mild reaction conditions. In contrast, the corresponding noncatalyzed cycloadditions for three substrates in the latter category require higher temperatures and exhibit low levels of stereocontrol.