RESUMO
We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.
RESUMO
Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.
Assuntos
Encéfalo , Quinases Associadas a Receptores de Interleucina-1 , Inibidores de Proteínas Quinases , Animais , Cães , Masculino , Camundongos , Ratos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Descoberta de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties.
Assuntos
Quinases Associadas a Receptores de Interleucina-1 , AVC Isquêmico , Camundongos , Animais , Humanos , Transdução de Sinais , Citocinas , Pirimidinas/farmacologia , Pirimidinas/uso terapêuticoRESUMO
Pyridones are versatile building blocks in organic synthesis and a privileged motif in drug discovery. However, N-substituted 2-pyridones bearing an α-tertiary carbon, cyclopropyl, or heterocycle off of the pyridone nitrogen atom remain challenging to prepare. Herein, we describe the efficient synthesis of a large variety of N-substituted 2-pyridones from ethyl nitroacetate and readily available primary amine building blocks, which can be utilized on a large scale and in parallel medicinal chemistry applications.
Assuntos
Aminas , Piridonas , Carbono , Técnicas de Química Sintética , Química FarmacêuticaRESUMO
Although the practice of using rapid-acting subcutaneous insulin for the management of mild-to-moderate diabetic ketoacidosis is becoming increasingly popular, the continuous insulin infusion remains widely utilized, and its real-world applicability and safety on a medical surgical unit (Med Surg) and observation level of care are unclear. We assessed whether a continuous insulin infusion protocol for mild-to-moderate diabetic ketoacidosis on Med Surg/observation level of care over a 6.5-year period was associated with adverse outcomes. A retrospective cohort study of adults hospitalized with mild-to-moderate diabetic ketoacidosis was conducted at 2 community hospitals in Northern California, USA, from January 2014 to May 2020. Demographic and clinical variables were collected using an electronic health record. Admission to Med Surg/observation was compared to intensive care unit admission for the outcomes of 30-day readmission, presence of hypoglycemia, rate of hypoglycemic episodes, in-hospital and 30-day mortality, and length of stay using bivariate analysis. Among 227 hospital encounters (mean age 41 years, 52.9% women, 79.3% type 1 diabetes, 97.4% utilization of continuous insulin infusion), 19.4% were readmitted within 30 days, and 20.7% developed hypoglycemia. For Med Surg/observation encounters compared to the intensive care unit, there were no statistically significant differences in the risk of readmission (RR 1.48, 95% CI, 0.86-2.52), hypoglycemia (RR 1.17, 95% CI, 0.70-1.95), or increased length of stay (RR 0.71, 95% CI, 0.55-1.02); there was a lower risk of hypoglycemic events during hospitalization (RR 0.69, 95% CI, 0.54-0.96). Continuous insulin infusion utilization may be a safe option for treatment of mild-to-moderate diabetic ketoacidosis on Med Surg/observation level of care. Further investigation is needed.
Assuntos
Diabetes Mellitus , Cetoacidose Diabética , Hipoglicemia , Adulto , Diabetes Mellitus/tratamento farmacológico , Cetoacidose Diabética/terapia , Feminino , Hospitais , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Estudos RetrospectivosRESUMO
Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid, and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression as well as a target for neurodegenerative diseases, including Alzheimer's. Moreover, knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS (amyotrophic lateral sclerosis) and displays modest motor benefits in an SOD1 ALS mouse model. To further validate whether inhibiting PLD is beneficial for the treatment of ALS, a brain penetrant small molecule inhibitor with suitable PK properties to test in an ALS animal model is needed. Using a combination of ligand-based drug discovery and structure-based design, a dual PLD1/PLD2 inhibitor was discovered that is single digit nanomolar in the Calu-1 cell assay and has suitable PK properties for in vivo studies. To capture the in vivo measurement of PLD inhibition, a transphosphatidylation pharmacodynamic LC-MS assay was developed, in which a dual PLD1/PLD2 inhibitor was found to reduce PLD activity by 15-20-fold.
RESUMO
The chemokine Cxcl10 has been associated with poor prognosis in breast cancer, but the mechanism is not well understood. Our previous study has shown that CXCL10 was repressed by the ING4 tumor suppressor, suggesting a potential inverse functional relationship. We thus investigated a role for Cxcl10 in the context of ING4 deficiencies in breast cancer. We first analyzed public gene expression data sets and found that patients with CXCL10-high/ING4-low expressing tumors had significantly reduced disease-free survival in breast cancer. In vitro, Cxcl10 induced migration of ING4-deleted breast cancer cells but not of ING4-intact cells. Using inhibitors, we found that Cxcl10-induced migration of ING4-deleted cells required Cxcr3, Egfr, and the Gßγ subunits downstream of Cxcr3 but not Gαi. Immunofluorescent imaging showed that Cxcl10 induced early transient colocalization between Cxcr3 and Egfr in both ING4-intact and ING4-deleted cells, which recurred only in ING4-deleted cells. A peptide agent that binds to the internal juxtamembrane domain of Egfr inhibited Cxcr3/Egfr colocalization and cell migration. Taken together, these results presented a novel mechanism of Cxcl10 that elicits migration of ING4-deleted cells, in part by inducing a physical or proximal association between Cxcr3 and Egfr and signaling downstream via Gßγ. These results further indicated that ING4 plays a critical role in the regulation of Cxcl10 signaling that enables breast cancer progression.
Assuntos
Proteínas de Ciclo Celular/deficiência , Quimiocina CXCL10/metabolismo , Receptores CXCR3/metabolismo , Proteínas Supressoras de Tumor/deficiência , Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Quimiocina CXCL10/genética , Receptores ErbB/metabolismo , Genes Supressores de Tumor/fisiologia , Proteínas de Homeodomínio , Humanos , Receptores CXCR3/genéticaRESUMO
Chronic rheumatic diseases often occur in women of reproductive age, and the effect rheumatic disease has on pregnancy varies depending on the condition. Medical management of rheumatic diseases during pregnancy may prevent joint or organ damage and minimize the adverse effects of the disease itself on pregnancy outcomes. Each patient requires individual assessment to control disease activity while minimizing or avoiding medications with potential maternal or fetal toxicity. An open discussion with shared decision making between patients, obstetricians, rheumatologists, and pharmacists is imperative to create an individualized treatment plan that meets patients' goals. This article will review the current literature for use of disease modifying antirheumatic drugs and biologics during pregnancy and lactation, providing health care professionals with the most up-to-date information available.
Assuntos
Antirreumáticos/uso terapêutico , Complicações na Gravidez/tratamento farmacológico , Doenças Reumáticas/tratamento farmacológico , Antirreumáticos/efeitos adversos , Aleitamento Materno , Feminino , Humanos , Lactação/efeitos dos fármacos , Gravidez , Resultado da GravidezRESUMO
Phospholipase D enzymes (PLDs) are ubiquitous phosphodiesterases that produce phosphatidic acid (PA), a key second messenger and biosynthetic building block. Although an orthologous bacterial Streptomyces sp. strain PMF PLD structure was solved two decades ago, the molecular basis underlying the functions of the human PLD enzymes (hPLD) remained unclear based on this structure due to the low homology between these sequences. Here, we describe the first crystal structures of hPLD1 and hPLD2 catalytic domains and identify novel structural elements and functional differences between the prokaryotic and eukaryotic enzymes. Furthermore, structure-based mutation studies and structures of inhibitor-hPLD complexes allowed us to elucidate the binding modes of dual and isoform-selective inhibitors, highlight key determinants of isoenzyme selectivity and provide a basis for further structure-based drug discovery and functional characterization of this therapeutically important superfamily of enzymes.
Assuntos
Fosfolipase D/ultraestrutura , Sequência de Aminoácidos , Domínio Catalítico , Desenho de Fármacos , Humanos , Isoenzimas/metabolismo , Fosfolipase D/metabolismo , Fosfolipase D/fisiologia , Diester Fosfórico Hidrolases/metabolismo , Relação Estrutura-AtividadeRESUMO
Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit NaV1.7 and demonstrate high levels of selectivity over other NaV isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective NaV1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over NaV1.5 and favorable pharmacokinetics in rodents.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior.
Assuntos
Amidas/farmacologia , Descoberta de Drogas , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Amidas/síntese química , Amidas/química , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The voltage-gated sodium channel NaV1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of NaV1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat NaV1.7 versus human NaV1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse NaV1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement.
Assuntos
Benzoxazinas/química , Benzoxazinas/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Benzoxazinas/farmacocinética , Benzoxazinas/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Dor/tratamento farmacológico , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
Several reports have recently emerged regarding the identification of heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. The optimization of a series of internal NaV1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities. The key to achieving this within a series prone to transporter-mediated clearance was the identification of a small range of optimal cLogD values and the discovery of subtle PXR SAR that was not lipophilicity dependent. This enabled the identification of compound 20, which was advanced into a target engagement pharmacodynamic model where it exhibited robust reversal of histamine-induced scratching bouts in mice.
Assuntos
Isoquinolinas/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Animais , Linhagem Celular , Citocromo P-450 CYP3A/biossíntese , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Cães , Indução Enzimática , Histamina , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Receptor de Pregnano X , Prurido/induzido quimicamente , Prurido/prevenção & controle , Ratos , Receptores de Esteroides/agonistas , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologiaRESUMO
Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [ Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation . WO 2014201206, 2014 ] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Quinolonas/química , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Capsaicina , Linhagem Celular , Cães , Histamina , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Dor/induzido quimicamente , Dor/prevenção & controle , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Prurido/induzido quimicamente , Prurido/prevenção & controle , Quinolonas/administração & dosagem , Quinolonas/síntese química , Quinolonas/farmacocinética , Quinolonas/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologiaRESUMO
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00243.].
RESUMO
Human genetic evidence has identified the voltage-gated sodium channel NaV1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of NaV1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining NaV1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.
RESUMO
Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridonas/síntese química , Piridonas/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Animais , Antineoplásicos/farmacocinética , Cristalografia por Raios X , Desenho de Fármacos , Descoberta de Drogas , Humanos , Camundongos , Modelos Moleculares , Piridonas/farmacocinética , Relação Estrutura-Atividade , Triazóis/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
Assuntos
Descoberta de Drogas , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinolinas/farmacologia , Triazóis/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Triazóis/química , Triazóis/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The medicinal chemistry subgroup of the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.