Novel histone deacetylase 6 (HDAC6) selective inhibitors: a patent evaluation (WO2014181137)

Introduction: Histone deacetylases (HDACs) are known to deacetylate histones and other proteins, which makes HDAC inhibitors able to affect cell survival, cell signaling, transport, and gene expression. Those effects have been associated to the therapeutic success of HDAC inhibitors. Class I-selective or pan-HDAC inhibitors have been approved for cancer therapy by the US Food and Drug Administration (FDA). Moreover, HDAC6 selective inhibitors entered phase I and II clinical trials for treating multiple myeloma. The development of potent and selective HDAC inhibitors is a hot topic in current drug discovery.

Areas covered: The invention described in this patent (WO2014181137) is related to hydroxamic acid derivatives with inhibitory activity towards HDACs, their synthetic process and pharmaceutical formulations, as well as a method for treating patients suffering from a list of selected tumoral, inflammatory, cardiac and chronic disorders.

Expert opinion: The compounds disclosed within this patent are selective against HDAC6 and their structure is related to tubastatin A, a known HDAC6 selective inhibitor. They are newly synthesized diarylamines showing an improved selectivity profile compared to other diarylamines under clinical investigation.     

P-glycoprotein Inhibition Increases the Brain Distribution and Antidepressant-Like Activity of Escitalopram in Rodents

Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P-gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysis-based pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat, thereby showing that P-gp restricts escitalopram transport across the blood–brain barrier (BBB) in vivo. The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression.     

Thiol-Based Potent and Selective HDAC6 Inhibitors Promote Tubulin Acetylation and T-Regulatory Cell Suppressive Function

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Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.     

Evaluation of WO2017018805: 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors

Introduction: There are great potential in the development of selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine diseases, and other diseases associated with HDAC6 activity.

Areas covered: The application claims 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; disease of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities. Many of the exemplified compounds showed nanomole potency against HDAC6 and were more than 5000-fold selectivity for HDAC6 over HDAC1.

Expert opinion: These 1,3,4-oxadiazole sulfamide derivatives have a unique zinc-binding group (ZBG) that provide good leads for the discovery of potent selective HDAC6 inhibitors for the treatment of a variety of diseases associated with HDAC6 activity.     

Design,Synthesis and Molecular Docking Studies of Novel Indole–Pyrimidine Hybrids as Tubulin Polymerization Inhibitors

A series of novel hybrids of indole–pyrimidine‐containing piperazine moiety were designed, synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. The results indicated that most of these compounds possessed significant cytotoxic potency against four cancer cell lines, HT‐29, A549, MDA‐MB‐231 and MCF‐7. Particularly, the most promising compound 34 showed more potent and broad‐spectrum cytotoxic activities with the IC₅₀ values ranged from 5.01 to 14.36 μm against A549, MDA‐MB‐231 and MCF‐7 cell lines. Meanwhile, 34 also displayed the most potent tubulin polymerization inhibitory activity with IC₅₀ value of 11.2 μm . Furthermore, molecular docking analysis demonstrated 34 interacts and binds efficiently with the tubulin protein at the colchicine‐binding site. It was worth noting that the compound did not affect the normal human embryonic kidney cells, HEK‐293. These results suggest that this novel class of indole–pyrimidine hybrids may have potential to be developed as new a class of tubulin polymerization inhibitors.     

Novel investigational drugs targeting IL-6 signaling for the treatment of depression

Introduction: Elevated levels of IL-6 have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Convergent evidence suggests that IL-6 primarily mediates proinflammatory functions via the soluble IL-6 receptor/trans-signaling, and anti-inflammatory functions via a transmembrane receptor (IL-6R). A targeted approach to selectively inhibit IL-6 trans-signaling may offer putative antidepressant effects.

Areas covered: This review addresses three primary domains. The first focuses on the biological role of IL-6 within inflammation and its signal transduction pathways. The second addresses the potential contributions of IL-6 to the pathophysiology of MDD, and the mechanisms that may mediate these effects. Finally, the article outlines the therapeutic benefits of incorporating anti-inflammatory properties into the pharmacological treatment of MDD, and proposes inhibition of IL-6 signaling as a viable treatment strategy.

Expert opinion: To improve drug development for the treatment of MDD, there is a critical need to identify promising targets. Target identification will require guidance from a strategic framework such as The Research Domain Criteria, and convincing evidence relating known targets to brain function under both physiological and pathological conditions. Although current evidence provides rationale for administering anti-IL-6 treatments in MDD, further studies confirming safety, target affinity and therapeutic benefits are warranted.     

Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [¹⁸F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6. PET studies of [¹⁸F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals, with more pronounced changes identified in the cortex and hippocampus. The translatability of this radiotracer for AD in a potential human use was supported by additional studies, including similar uptake profiles in non-human primates, an increase of HDAC6 in AD-related human postmortem hippocampal tissues by Western blotting protein analysis, and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals. Collectively, our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.     

N6-甲基腺苷去甲基化酶小分子抑制剂的研究进展

N⁶-甲基腺苷（m⁶A）是RNA中最常见、最保守的修饰之一,也是目前表观遗传学热门研究靶点之一。哺乳动物细胞中的m⁶A修饰具有动态可逆性。m⁶A的异常与多种疾病的形成、发展有关。m⁶A去甲基化酶包括脂肪和肥胖相关蛋白（FTO）、Alkb家族同源蛋白5（ALKBH5）以及ALKBH3,负责催化RNA的m⁶A去除甲基化。抑制m⁶A去甲基化酶可调控m⁶A的水平,并在相关癌症中降低细胞存活率从而抑制肿瘤生长。因此,针对m⁶A去甲基化酶的小分子抑制剂研究成为抗肿瘤药物研究领域的热点。对m⁶A去甲基化酶相关的癌症等疾病进行综述,着重关注其小分子抑制剂的研究进展,将有利于增进对该领域的全面认识并为相关药物的进一步研发提供参考。     

Enhanced Bioavailability of Subcutaneously Injected Insulin by Pretreatment with Ointment Containing Protease Inhibitors

The present study was undertaken to develop an ointment preparation containing a protease inhibitor for stabilizing subcutaneously injected insulin. The ointment containing the protease inhibitor, gabexate mesilate or nafamostat mesilate, was applied to the skin around the insulin injection site. Three results were obtained. First, gabexate and nafamostat inhibited insulin degradation in subcutaneous tissue homogenates in vitro. Second, after application of gabexate or nafamostat ointment, an appreciable amount of gabexate or nafamostat appeared in the subcutaneous tissue of rats or hairless mice and their concentrations were comparable to those seen in the in vitro experiment. Third, insulin degradation at the subcutaneous injection site in the rat was depressed after pretreatment with gabexate or nafamostat ointment. Pretreatment with gabexate or nafamostat ointment increased the plasma immunoreactive insulin (IRI) levels and the hypoglycemic effect of insulin in healthy volunteers. These results indicate that gabexate or nafamostat ointments stabilize subcutaneously injected insulin.     

HDAC6 is critical for ketamine-induced impairment of dendritic and spine growth in GABAergic projection neurons

Ketamine is widely used in infants and children for anesthesia; both anesthetic and sub-anesthetic doses of ketamine have been reported to preferentially inhibit the GABAergic neurons. Medium spiny neurons (MSNs), the GABAergic projection neurons in the striatum, are vulnerable to anesthetic exposure in the newborn brain. Growth of dendrites requires a deacetylase to remove acetyl from tubulin in the growth cone to destabilize the tubulin. Histone deacetylase 6 (HDAC6) affects microtubule dynamics, which are involved in neurite elongation. In this study we used a human induced pluripotent stem cells (iPSCs)-derived striatal GABA neuron system to investigate the effects of ketamine on HDAC6 and the morphological development of MSNs. We showed that exposure to ketamine (1–500 μM) decreased dendritic growth, dendrite branches, and dendritic spine density in MSNs in a time- and concentration-dependent manner. We revealed that ketamine treatment concentration-dependently inhibited the expression of HDAC6 or aberrantly translocated HDAC6 into the nucleus. Ketamine inhibition on HDAC6 resulted in α-tubulin hyperacetylation, consequently increasing the stability of microtubules and delaying the dendritic growth of MSNs. Finally, we showed that the effects of a single-dose exposure on MSNs were reversible and lasted for at least 10 days. This study reveals a novel role of HDAC6 as a regulator for ketamine-induced deficits in the morphological development of MSNs and provides an innovative method for prevention and treatment with respect to ketamine clinical applications.     

Enantioselective synthesis and biological investigation of tetrahydro‐β‐carboline‐based HDAC6 inhibitors with improved solubility

Aberrant epigenetic changes in DNA methylation and histone modification by acetylation or deacetylation regulate the pathogenesis of many diseases. Especially selective inhibitors are getting more and more attention. We recently reported on a new class of potent and selective anti‐inflammatory and antirheumatic histone deacetylase 6 (HDAC6) inhibitors (e.g., Marbostat‐100). The attachment of a morpholinoethoxy part to the head group dramatically enhances the solubility, in particular the solubility in aqueous solutions, of the lead compound Marbostat‐100. Here, we present the enantioselective synthesis of small‐molecule compounds based on the tetrahydro‐β‐carboline core system with improved solubility, and the influence of the stereochemistry on the biological activity. The enantiomers were synthesized in good enantiomeric excess (ee) purity and were potent and selective HDAC6 inhibitors, whereas the S‐derivative S‐ 21 is clearly the eutomer. The potency of our selective HDAC6 inhibitors is demonstrated by K_i values in the range of 0.5–2 nM toward HDAC6, and the selectivity was proved in cellular assays by Western blot analysis taking ac‐tubulin as surrogate parameter.     

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1

We describe the identification and characterization of a series of covalent inhibitors of the C-terminal kinase domain (CTKD) of MSK1. The initial hit was identified via a high-throughput screening and represents a rare example of a covalent inhibitor which acts via an S_NAr reaction of a 2,5-dichloropyrimidine with a cysteine residue (Cys440). The covalent mechanism of action was supported by in vitro biochemical experiments and was confirmed by mass spectrometry. Ultimately, the displacement of the 2-chloro moiety was confirmed by crystallization of an inhibitor with the CTKD. We also disclose the crystal structures of three compounds from this series bound to the CTKD of MSK1, in addition to the crystal structures of two unrelated RSK2 covalent inhibitors bound to the CTKD of MSK1.     

A Double-Blind Comparison of Sertraline and Imipramine in Outpatients with Major Depression: Acute (8 Weeks) and Continuation (16 Weeks) Treatment

In a double-blind multicentre trial in patients with major depression, the efficacy and the tolerability of sertraline were compared to those of imipramine, during an 8-week acute treatment phase followed by a 16-week continuation treatment phase in treatment responders. A total of 104 patients who met DSM-III-R criteria for major depression, HAM-D 17-item≥18 and Raskin Depression score>Covi Anxiety score, were randomized to receive either sertraline or imipramine. The initial daily dosage of 50 mg of sertraline or imipramine was rapidly titrated upwards in increments of 50 mg/day at weekly intervals, tolerability permitting, to a maximum of 200 mg/day by the fourth week. Eighty-eight patients completed at least 3 weeks of treatment and were included in the efficacy evaluable population. Both treatment groups demonstrated similar improvements on depression and anxiety rating scales during acute treatment, however, sertraline demonstrated significantly more improvement relative to imipramine on the HAM-D and Covi Anxiety scales after 1 week of treatment. Sertraline was more effective (HAM-D 17-item, CGI-S, SCL-56 Total score, SCL-56 Depression score, Covi Anxiety score) than imipramine in reducing depressive symptoms at the end of 24 weeks of treatment. There were significant improvements in all rating scales at week 24 relative to week 8 in the sertraline group but not in the imipramine group. The SCL-56 Total score, SCL-56 Depression score, Raskin Depression score and Covi Anxiety score at week 24 relative to week 8 showed significantly greater improvement in the sertraline group compared to the imipramine group. Imipramine was associated with a significantly higher incidence of dry mouth, sweating, constipation, palpitations, and a significantly higher heart rate and blood pressure. Sertraline was associated with a significantly higher incidence of diarrhoea/loose stools and insomnia. This study demonstrated a faster onset of therapeutic effect for sertraline relative to imipramine, reflecting the initiation of sertraline in a therapeutic dose of 50 mg/day and the need for gradual titration of imipramine to a therapeutic dose, at the beginning of treatment. Although efficacy was similar in both treatment groups at the end of the 8 weeks of acute therapy, sertraline-treated patients continued to manifest gradual improvements in depressive and anxiety symptoms during the 16 weeks of continuation therapy such that sertraline-treated patients were significantly more improved at the end of 24 weeks of therapy. © 1997 John Wiley & Sons, Ltd.     

Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group

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Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2 Inhibitors with Improved Pharmacokinetic Properties

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Identification of Novel Anaplastic Lymphoma Kinase (ALK) Inhibitors Using a Common Feature Pharmacophore Model Derived from Known Ligands Crystallized with ALK

In this investigation, a common feature pharmacophore model of anaplastic lymphoma kinase inhibitors was developed based on several known anaplastic lymphoma kinase inhibitors that were co‐crystallized with anaplastic lymphoma kinase. The established pharmacophore model Hypo1 was carefully validated and then adopted to screen two in silico chemical databases, Specs (202 408 compounds) and Enamine (1 105 894 compounds), for retrieving novel anaplastic lymphoma kinase inhibitors. The hit compounds were further filtered using a fast bumping‐check tool and molecular docking. Finally, 25 compounds were selected and purchased from market. The bioactivity of these compounds was firstly measured at the cellular level against a typical anaplastic lymphoma kinase mutant‐driven cancer cell line, Karpas299. And six of them showed a good anti‐viability activity. The kinase inhibitory potency against the recombinant human anaplastic lymphoma kinase kinase was tested to the most active compound at the cellular level, T0508‐5181 (from Specs), which gave a half maximal inhibitory concentration (IC₅₀) of 5.3 μm .     

Predictors of systemic therapy sequences following a CDK 4/6 inhibitor-based regimen in post-menopausal women with hormone receptor positive,HEGFR-2 negative metastatic breast cancer

Objective: To identify systemic treatment in the real-world following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDKi) among post-menopausal women with hormone receptor positive, human epidermal growth factor receptor 2 Negative (HR+/HER2–) metastatic breast cancer (mBC).

Methods: Post-menopausal women with HR+/HER2– mBC were identified from MarketScan claims databases between January 1, 2012 and October 31, 2017. Eligible mBC patients who received a CDKi-based line of therapy following metastasis diagnosis were selected. A line of therapy ended at the earlier of systemic therapy discontinuation, switch to new treatment, or censoring.

Results: In total, 525 patients that received systemic therapy after a CDKi-based line were included (39.6% transitioned from use of a CDKi-based regimen in first line following metastasis diagnosis to any second line, and 60.4% shifted from a CDKi-based [second, third, or fourth line] to a subsequent line). Of post-CDKi second line regimens (n?=?208), 38.0% were endocrine only, 35.6% were chemotherapy-based, 14.4% were everolimus-based, 9.6% were also CDKi-based line, and 2.4% were others. After adjusting for demographic and clinical characteristics, patients transitioning from a CDKi-based line to chemotherapy (vs others) had a trend of being more likely to have recurrent rapidly progressing disease, and were significantly less likely to have the prior CDKi-based line in combination with an AI (both p?<?.05).

Conclusions: This population-based study suggests that rapidly progressing disease, metastatic site location, age, and endocrine therapy partner may be predictive of subsequent systemic therapy regimen selection after progression on a CDKi-based line therapy in patients with HR+/HER2– mBC.