Patent Evaluation: Poly(ADP-ribose)polymerase inhibitors as potential antimicrobial agents

Summary

Novelty: Substituted benzoic acids, benzamides and esters are disclosed for use against HIV. They are said to exhibit nuclear ADP-ribosyl transferase activity and are related to known inhibitors. Potential use in trypanosomiasis and cancer is also claimed.

Biology: There are no detailed biological data to support the claims. Fifteen synthetic examples are included. A typical preferred compound is 4-methylureidobenzamide.

Structure:     

Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics

The year of 2005 was a watershed in the history of poly(ADP-ribose) polymerase (PARP) inhibitors due to the important findings of selective killing in BRCA-deficient cancers by PARP inhibition. The findings made PARP inhibition one of the most promising new therapeutic approaches to cancers, especially to those with specific defects. With AZD2281 and BSI-201 entering phase III clinical trials, the final application of PARP inhibitors in clinic would come true soon. This current paper will review the major advances in targeting PARP for cancer therapy and discuss the existing questions, the answers to which may influence the future of PARP inhibitors as cancer therapeutics.     

SRC inhibitors as potential therapeutic agents for human cancers

Selective inhibitors of the Src family of protein tyrosine kinases have been developed as therapeutic agents for human tumors, some of which are now in various stages of clinical trial. In this review, recently described novel small molecule ATP-competitive Src inhibitors are discussed, with an emphasis on their potential use as therapeutic inhibitors for advanced-stage malignancies.     

New inhibitors of poly(ADP-ribose) polymerase and their potential therapeutic targets

Poly(ADP-ribose) polymerase (PARP) is a DNA-binding protein that is activated by nicks in the DNA molecule. It regulates the activity of various enzymes, including itself, that are involved in the control of DNA metabolism. Evidence obtained with both benzamide and isoquinolinone PARP inhibitors and the PARP-1(^-/-) phenotype, clearly indicate that PARP plays an important role in NO/ROS-induced cell damage during inflammation, ischaemia and neurodegeneration. PARP is involved in the maintenance of genomic stability and PARP inhibition may also potentiate the cytotoxic action of agents used in cancer therapy. Benzamides, although not very potent (IC₅₀ ~ 20 – 50 μM) PARP inhibitors, have been widely used to probe PARP functions, because of their lack of toxicity both in vitro and in vivo, even at high doses. In the early 1990s, a new class of very potent PARP inhibitors (i.e., at least 100-fold more potent thatn benzamide), the dihydroisoquinolinones, benzamide derivatives with the carbamoyl group constrained into the antiorientation, was discovered. At the same time, a large structure–activity surevey identified over 13 chemical classes of PARP inhibitors, the most potent calss sharing a common structural feature, the presence of a carbonyl group built into a polyaromatic heterocyclic skeleton or a carbamoyl group attached to an aromatic ring. Recently, a better knowledge of the PARP catalytic domain and the use of its crystal structure have led to the design and synthesis of the tricyclic lactam indoles, active at low nanomolar concentrations, and with favourable physical properties and in vivo characteristics. In the last few years the interest in PARP as a therapeutic target has been rapidly growing. This article reviews the patents filed for new PARP inhibitors over the last three years, up to February 2002, and their development status.     

Rho kinase inhibitors as potential therapeutic agents for cardiovascular diseases

RhoA and Rho-kinase (ROCK) participate in diverse cellular signaling functions such as smooth muscle contraction, cytoskeleton rearrangement, and cell migration and proliferation. In smooth muscle, ROCK plays an important role in calcium sensitization, an event that controls vascular vessel tone. Recent studies using ROCK inhibitors along with cellular and molecular biology techniques have revealed a pivotal role of this enzyme in many other aspects of cardiovascular function. This review will focus on the current understanding of Rho/ROCK signaling pathways and discuss the use of ROCK inhibitors as therapeutic agents for cardiovascular diseases ranging from hypertension to atherosclerosis.     

Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015–2018)

Introduction: Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine-protein kinase, an enzyme that in humans is encoded by the TYK2 gene. Tyk2, together with three other family subtypes, namely, Jak1, Jak2, and Jak3, belong to the JAK family. Before 2014, far more publications and patents appeared in public domain attributing to the development of selective Jak2 and Jak3 inhibitors than those for selective Tyk2 and Jak1 inhibitors.

Areas covered: This review sought to give an overview of patents related to small molecule selective Tyk2 inhibitors published from 2015 to 2018. The article also covers clinical activities of small molecule selective Tyk2 inhibitors in recent years.

Expert opinion: As a key component of the JAK-STAT signaling pathway, Tyk2 regulates INFα, IL12, and IL23. Selective inhibition of Tyk2 can provide pharmacological benefits in the treatment of many diseases such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cancer, and diabetes. The selectivity against other Jak family subtypes (such as Jak2) is crucial in order to minimize the potential side effects and to maximize the desired pharmacological effects. In this context, this review of recent selective Tyk2 inhibitor patents may prove valid, interesting, and promising within the therapeutic paradigm.     

Thalidomide derived immunomodulatory drugs (IMiDs) as potential therapeutic agents

Thalidomide is known to be effective in the treatment of a number of conditions, including leprosy and various cancers. The exact mechanisms of action remain unclear although these are known to include anti-tumour necrosis factor (TNF)-alpha, T cell costimulatory, anti-angiogenic and anti-tumour activities. However, thalidomide is being superceded by novel structural derivatives which have been designed to have improved immunomodulatory activity and side effect profiles. These are currently being characterised and some are entering the clinic in phase I/II studies. One novel group of structural analogues are classified as the Immunomodulatory Drugs (IMiDs). This review describes the emerging immunological, anti-angiogenic and direct anti-tumour properties of thalidomide and the characterisation and clinical application of its IMiD analogues. We describe the laboratory studies which have led to the characterisation and development of IMiDs into potentially clinically relevant drugs. Early trial data suggests that these compounds may themselves become established therapies, particularly in certain cancers. Furthermore, ongoing studies will determine how best to apply these compounds to the appropriate clinical settings. We will describe the various clinical studies of lead compounds that are in progress and speculate as to the potential and future development of these exciting compounds.     

通过调节高迁移率族蛋白B1治疗相关疾病的药物研究进展

高迁移率族蛋白B1（high-mobility group box-1,HMGB1）是一种非组蛋白染色质结合蛋白,参与核小体结构的维持和基因转录调控。它可因受到多种因素刺激而释放到细胞外环境。胞外的HMGB1参与多种慢性炎症、自身免疫性疾病以及癌症的发展。目前已知HMGB1与细胞表面的糖化终末产物受体（receptor for advanced glycation end products, RAGE）的相互作用是这些疾病发展的一个重要信号通路,因此,抑制HMGB1与RAGE的相互作用及其调节通路可能是炎症调节以及肿瘤治疗的重要靶点。本文综述了在抑制HMGB1及其与之相关的炎症过程（尤其是HMGB1-RAGE信号通路）中的最新研究进展,以及通过调节HMGB1治疗相关疾病的药物的现状和应用前景。     

Adenosine antagonists as potential therapeutic agents

The methylxanthine caffeine has been identified in more than 60 plant species and has been in human use for its various therapeutic actions for many hundreds of years and perhaps, with the exception of aspirin and related compounds, is the most widely consumed drug today. Pharmacologically, the xanthines are prototypic inhibitors of the enzyme, cyclic nucleotide phosphodiesterase, are calcium mobilizers and have been reported to inhibit the enzymes, monoamine oxidase and cyclooxygenase as well as affect uptake of the putative neuromodulator, adenosine. However, many of the therapeutic effects ascribed to caffeine are due to its selective ability to antagonize the actions of adenosine. Many xanthines, especially those substituted in the 8-position with a phenyl derivative, are potent and selective adenosine antagonists. The xanthine adenosine antagonists have mild psychostimulant, analgesic adjuvant, diuretic, cardiotonic and antiasthmatic activity. Adenosine antagonists also have nootropic activity. A major limiting factor to the development of this class of compound has been in the lack of selectivity for either of the major classes of adenosine receptor. Several non-xanthines including the pyrazolopyrimidine, DJB-KK, the pyrazoloquinoline, CGS 8216 and the pyrazolopyridine, etazolate have been shown to have adenosine antagonist activity. The triazoloquinazoline, CGS 15943 A has been identified as the first, potent (IC50 = 3 nM) nonxanthine, A2-selective adenosine antagonist while the phenylquinazoline, HTQZ, has 25-fold selectivity for the A2 receptor. The availability of such novel entities may permit the development of a new class of therapeutic agents able to affect neuromodulator, as opposed to neurotransmitter, function.     

Quinazolinone analogs as potential therapeutic agents

Quinazolinone scaffold has been considered as a magic moiety possessing myriad spectrum of medicinal activities. Diversity of biological response profile has attracted considerable interest of several researchers across the globe to explore this skeleton for its assorted therapeutic significance. Various novel classes of structurally different quinazolinones have been designed and synthesized depicting potential interventions such as antibacterial, antifungal, antiviral, anticonvulsant, CNS depressant, antiinflammatory, antihistaminic, anticancer and so on. Moreover, the nucleus constitutes an integral structural component in a number of drugs currently employed in several clinical therapies. The present paper is an earnest attempt to provide an insight view on the current medicinal aspects of quinazolinone heterocycles alongwith brief discussion of their chemistry.     

Poly(ADP-ribose) polymerase inhibitors in the prevention of neuronal cell death

Poly(ADP-ribose) polymerase is a nucleic enzyme that promotes energy-dependent repair of DNA, thus helping to protect against DNA fragmentation. Overactivation of PARP, for example in the context of apoptosis, may contribute to neuronal cell death. This article briefly reviews claims for PARP inhibitors as agents for the prevention of neuronal cell death, registered in the period 1998 – December 2001. Biological data are sparse in these patents, few claims are backed by in vitro biochemical data and fewer still with in vivo animal model data. The latter have used animal models of ischaemia rather than of neurodegeneration. The place of PARP inhibitors as a clinical therapy to prevent neuronal cell death remains to be determined.     

Selective COX-2 inhibitors as chemopreventive and therapeutic agents

Selective cyclooxygenase-2 (COX-2) inhibitors have received increasing attention for their role in the prevention and treatment of cancer. Considerable preclinical data support this use. Furthermore, clinical studies have shown that this enzyme is upregulated in a variety of premalignant and malignant states and that its inhibition can decrease colon polyp formation in patients with familial adenomatous polyposis. A number of studies are now investigating the use of COX-2 inhibitors to prevent or treat a number of different cancers. These ongoing trials will determine whether these agents are useful in the treatment of cancer.     

Proteasome inhibitors as potential novel anticancer agents

Ubiquitin/proteasome-dependent proteolysis plays an essential role in degrading regulatory proteins and thereby controlling processes of cell proliferation and cell death (apoptosis). Most recent experiments using cell cultures and mouse models have demonstrated that proteasome inhibitors induce cancer cell apoptosis and therefore inhibit tumor growth. The proteasome inhibitors have the following unique features: (i) greater apoptosis-inducing potency when tested in various human tumor cell lines than current anticancer drugs; (ii) ability to selectively target transformed and tumor, but not normal, human cells; and (iii) ability to overcome tumor cell resistance to cytotoxic therapies. We suggest that proteasome inhibitors have potential use as novel anticancer agents.     

Methods for synthesis and uses of inhibitors of ghrelin O-acyltransferase inhibitors as potential therapeutic agents for obesity and diabetes

The patent claims inhibitors of ghrelin-O-acyltransferase enzyme. These inhibitors were designed as bisubstrate analogs of the enzymatic reaction and were coupled with one of the peptides able to cross cell membranes, the 11-mer Tat peptide. The compound GO-CoA-Tat was studied in vitro and in vivo; after intraperitoneal administration, it enhances insulin response to a glucose load and leads to a statistically significant weight loss in mouse fed with a high fat diet.