RESUMO
A robust, practical, and scalable approach for the construction of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 via the addition of Grignard reagents to 4-amino-2-chloronicotinonitrile (15) was developed. Starting with various Grignard reagents, a wide range of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 were conveniently synthesized in moderate-to-good yields through addition-acidolysis-cyclocondensation. In addition, the robustness and applicability of this synthetic route was proven on a 100 g scale, which would enable convenient sample preparation in the preclinical development of 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidates.
Assuntos
Antineoplásicos/química , Indicadores e Reagentes/química , Naftiridinas/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Conventional methods of drug design require compromise in the form of side effects to achieve sufficient efficacy because targeting drugs to specific organs remains challenging. Thus, new strategies to design organ-specific drugs that induce little toxicity are needed. Based on characteristic tissue niche-mediated drug distribution (TNMDD) and patterns of drug metabolism into specific intermediates, we propose a strategy of distribution- and metabolism-based drug design (DMBDD); through a physicochemical property-driven distribution optimization cooperated with a well-designed metabolism pathway, SH-337, a candidate potassium-competitive acid blocker (P-CAB), was designed. SH-337 showed specific distribution in the stomach in the long term and was rapidly cleared from the systemic compartment. Therefore, SH-337 exerted a comparable pharmacological effect but a 3.3-fold higher no observed adverse effect level (NOAEL) compared with FDA-approved vonoprazan. This study contributes a proof-of-concept demonstration of DMBDD and provides a new perspective for the development of highly efficient, organ-specific drugs with low toxicity.
RESUMO
Several secondary tropomyosin receptor kinase (TRK) mutations located in the solvent front, xDFG, and gatekeeper regions, are a common cause of clinical resistance. Mutations in the xDFG motif in particular limit sensitivity to second-generation TRK inhibitors, which represent an unmet clinical need. We designed a series of 3-pyrazolyl-substituted pyrazolo[1,5-a]pyrimidine derivatives toward these secondary mutations using ring-opening and scaffold-hopping strategies. Compound 5n was the most potent, with IC50 values of 2.3 nM, 0.4 nM, and 0.5 nM against TRKAG667C, TRKAF589L, and TRKAG595R, compared to selitrectinib with IC50 values of 12.6 nM, 5.8 nM, and 7.6 nM, respectively (approximately 5.4, 14.5, and 15.2-fold increases). Furthermore, 5n displayed favorable pharmacokinetic properties and satisfactory antitumor efficacy (tumor growth inhibition of 97% at 30 mg/kg and 73% at 100 mg/kg) in TRKAWT and TRKAG667C xenograft mouse models. Collectively, 5n is a promising TRK inhibitor lead compound for overcoming clinically acquired resistance to second-generation inhibitors, particularly for resistant tumors harboring the TRKAG667C mutation in the xDFG motif.
Assuntos
Antineoplásicos , Neoplasias , Animais , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptor trkARESUMO
Mutation-induced resistance to targeted drug treatment poses a serious threat to successful chemotherapy. Multiple mutations underlying drug resistance remain a largely unsolved scientific issue. Tropomyosin receptor kinases (TRKs) are promising therapeutic targets for several malignant human cancers, but they have become less effective due to multiple resistance mutations. Thus, TRKs are representative cases to explore the problem of multiple resistance mutations. Here, we proposed a conformational adjustment strategy of drug design to overcome multiple resistance mutations in cancer treatments. A representative inhibitor, TIY-7, exhibited remarkable inhibitory activity against five TRK mutants, showing an IC50 value of 1.1 nM against the most severe mutant TRKA-G595R. Moreover, it displayed superior tumor growth inhibitory activity compared with the clinically used drug selitrectinib. These results validated our strategy to design a new inhibitor structure to overcome multiple resistance mutations.
Assuntos
Neoplasias , Receptor trkA , Desenho de Fármacos , Humanos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Receptor trkA/genética , TropomiosinaRESUMO
Coronavirus disease 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still a pandemic around the world. Currently, specific antiviral drugs to control the epidemic remain deficient. Understanding the details of SARS-CoV-2 structural biology is extremely important for development of antiviral agents that will enable regulation of its life cycle. This review focuses on the structural biology and medicinal chemistry of various key proteins (Spike, ACE2, TMPRSS2, RdRp and Mpro) in the life cycle of SARS-CoV-2, as well as their inhibitors/drug candidates. Representative broad-spectrum antiviral drugs, especially those against the homologous virus SARS-CoV, are summarized with the expectation they will drive the development of effective, broad-spectrum inhibitors against coronaviruses. We are hopeful that this review will be a useful aid for discovery of novel, potent anti-SARS-CoV-2 drugs with excellent therapeutic results in the near future.
Assuntos
Antivirais/química , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Proteínas da Matriz Viral/química , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/patologia , COVID-19/virologia , Reposicionamento de Medicamentos , Humanos , SARS-CoV-2/isolamento & purificação , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas da Matriz Viral/metabolismo , Internalização do Vírus/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Tropomyosin receptor kinase (TRK) inhibition is an effective therapeutic approach for treatment of a variety of cancers. Despite the use of first-generation TRK inhibitor (TRKI) larotrectinib (1) resulting in significant therapeutic response in patients, acquired resistance develops invariably. The emergence of secondary mutations occurring at the solvent-front, xDFG, and gatekeeper regions of TRK represents a common mechanism for acquired resistance. However, xDFG mutations remain insensitive to second-generation macrocyclic TRKIs selitrectinib (3) and repotrectinib (4) designed to overcome the resistance mediated by solvent-front and gatekeeper mutations. Here, we report the structure-based drug design and discovery of a next-generation TRKI. The structure-activity relationship studies culminated in the identification of a promising drug candidate 8 that showed excellent in vitro potency on a panel of TRK mutants, especially TRKAG667C in the xDFG motif, and improved in vivo efficacy than 1 and 3 in TRK wild-type and mutant fusion-driven tumor xenograft models, respectively.
Assuntos
Descoberta de Drogas , Compostos Macrocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptor trkA/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Modelos Moleculares , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Receptor trkA/genética , Receptor trkA/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing quinoline moiety in block A were designed and synthesized based on the structures of Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently advanced into preclinical research.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinolinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Quinolinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
New 8-chloro-2-phenyl-2,7-naphthyridin-1(2H)-one building blocks bearing diverse substitutes on the 2-phenyl group were synthesized via an efficient diaryliodonium salt-based N-arylation strategy with the advantage of mild conditions, short reaction times, and high yields. A small combinatorial library of 8-amino substituted 2-phenyl-2,7-naphthyridin-1(2H)-one was further conveniently constructed based on the above chlorinated naphthyridinones and substituted aniline. Preliminary biochemical screening resulted in the discovery of the new 2,7-naphthyridone-based MET/AXL kinase inhibitors. More importantly, 17c (IC50,MET of 13.8 nM) or 17e (IC50,AXl of 17.2 nM) and 17i (IC50,AXl of 31.8 nM) can efficient selectively inhibit MET or AXL kinase, respectively, while commercial cabozantinib showed no selectivity. The further exploration of the 8-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one combinatorial library would significantly accelerate the discovery of more potent and selective inhibitors against diverse kinases.
Assuntos
Descoberta de Drogas , Oniocompostos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Oniocompostos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade , Receptor Tirosina Quinase AxlRESUMO
A potent and novel MET inhibitor, 5-((4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)amino)-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-ones (8), was designed and synthesized via a scaffold-hopping strategy of a 2,7-naphthyridinone MET kinase inhibitor 7. Lead compound 8 had good potency (IC50 of 9.8â¯nM), but unfavorable pharmacokinetic profiles (Fâ¯=â¯12%, CLâ¯=â¯5.0â¯L/h/kg). Systematic structural optimization of compound 8 resulted in 9g (MET, IC50â¯=â¯of 9.8â¯nM) with a comparable MET potency to that of compound 2 and a favorable pharmacokinetic profile (Fâ¯=â¯63%, CLâ¯=â¯0.12â¯L/h/kg). Further study of the derivatization of N(1) amine group of 9g led to the discovery of 23a with good MET potency (IC50 of 7.1â¯nM), promising VEGFR-2 selectivity (3226-fold), and a markedly drug-likeness improvement (Fâ¯=â¯57.7%, CLâ¯=â¯0.02â¯L/h/kg). The excellent VEGFR-2 selectivity and favorable drug-likeness of 23g suggest that the 1,6-naphthyridine moiety could be used as a new scaffold for kinase inhibitor discovery.
Assuntos
Antineoplásicos/farmacologia , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC50 = 9.0 nM), human microsomal metabolic stability (t1/2 = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development.
Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Naftiridinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinazolinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Feminino , Humanos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Quinazolinas/síntese química , Quinazolinas/metabolismo , Ratos , Relação Estrutura-Atividade , Termodinâmica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
As part of our effort to develop new molecular targeted antitumor drug, a novel 2,7-naphthyridone-based MET kinase inhibitor, 8-((4-((2-amino-3-chloropyridin-4-yl)oxy)- 3-fluorophenyl)amino)-2-(4-fluorophenyl)-2,7-naphthyridin-1(2H)-one (13f), was identified. Knowledge of the binding mode of BMS-777607 in MET led to the design of new inhibitors that utilize novel 2,7-naphthyridone scaffold to conformationally restrain the key pharmacophoric groups (block C). Detailed SAR studies resulted in the discovery of a new MET inhibitor 13f, displaying favorable in vitro potency and oral bioavailability. More importantly, 13f exhibited excellent in vivo efficacy (tumor growth inhibition/TGI of 114% and 95% in 50â¯mg/kg, respectively) both in the U-87 MG and HT-29 xenograft models. The favorable drug-likeness of 13f indicated that 2,7-naphthyridinone may be used a promising novel scaffold for antitumor drug development. The preclinical studies of 13f are under way.