Potential functional and pathological side effects related to off-target pharmacological activity

In spite of the availability of a large number of anti-inflammatory and analgesic agents, fighting pain and inflammation remains a common problem. The current review article discusses the need of novel therapeutic targets for risk-free anti-inflammatory and analgesic therapy and summarizes some new agents in various stages of drug discovery pipeline. Pyridazin-3(2H)-ones are nitrogen-rich heterocyclic compounds of considerable medicinal interest due to their diverse biological activities. The current review article focuses on progressive development of this attractive scaffold for the design and synthesis of new pyridazinone-based anti-inflammatory and analgesic agents. Mechanistic insights into the anti-inflammatory and analgesic properties of pyridazinone derivatives and various synthetic techniques used for their synthesis are also described.

Pyridazinone: an attractive lead for anti-inflammatory and analgesic drug discovery

The cyclic nucleotides (cN), cAMP and cGMP, are key second messengers that mediate the intracellular effects of many signals known as “first messengers”, including environmental signals such as photons for vision and chemicals for taste, as well as hormones, paracrine factors, neurotransmitters, or autocrine factors. Many “first messengers” affect the level of cAMP and/or cGMP thereby initiating increased or decreased signaling selectively through cAMP- or cGMP-signaling pathways. cAMP and cGMP are synthesized by adenylyl cyclases and guanylyl cyclases, respectively, and degraded by a large superfamily of cN phosphodiesterases (PDE). Following the discovery of cAMP (Rall and Sutherland 1958), the search for the role of cAMP in modulating a wide variety of biological processes quickly ensued. Cyclic GMP was discovered in 1963, but many years elapsed before cGMP signaling proved to be a powerful and selective physiological process in its own right. Sutherland and colleagues reasoned that for cNs to be biologically relevant, there must be a mechanism for their removal from the cellular milieu. In 1958 they reported that heart extracts contained PDE activity that dampened or terminated the action of cAMP, and this PDE activity was blocked by methylxanthines, i.e., caffeine and theophylline (Butcher and Sutherland 1962). This was the first report of PDE action and identification of PDE inhibitors.

Cyclic GMP-hydrolyzing phosphodiesterases.

Research using animal models of asthma is currently dominated by mouse models. This has been driven by the comprehensive knowledge on inflammatory and immune reactions in mice, as well as tools to produce genetically modified mice. Many of the identified therapeutic targets influencing airway hyper-responsiveness and inflammation in mouse models, have however been disappointing when tested clinically in asthma. It is therefore a great need for new animal models that more closely resemble human asthma. The guinea pig has for decades been used in asthma research and a comprehensive table of different protocols for asthma models is presented. The studies have primarily been focused on the pharmacological aspects of the disease, where the guinea pig undoubtedly is superior to mice. Further reasons are the anatomical and physiological similarities between human and guinea pig airways compared with that of the mouse, especially with respect to airway branching, neurophysiology, pulmonary circulation and smooth muscle distribution, as well as mast cell localization and mediator secretion. Lack of reagents and specific molecular tools to study inflammatory and immunological reactions in the guinea pig has however greatly diminished its use in asthma research. The aim in this position paper is to review and summarize what we know about different aspects of the use of guinea pig in vivo models for asthma research. The associated aim is to highlight the unmet needs that have to be addressed in the future.

/pdf/back-to-the-future-re-establishing-guinea-pig-in-vivo-asthma-3bicpx4rc3.pdf

Back to the future: re-establishing guinea pig in vivo asthma models

Intermittent claudication (IC) is one of the most frequent forms of lower extremity peripheral arterial disease (PAD) and is most commonly caused by arterial atherosclerosis. Its clinical manifestation includes fatigue, discomfort, or pain occurring in limb muscles due to exercise-induced ischemia, thus limiting the ability of IC patients to walk and exercise. In addition to lifestyle changes (diet, exercise, and smoking cessation), pharmacological treatments are needed. Pathologically, atherosclerotic lesions cause a mismatch in oxygen supply and metabolic demand in the leg muscles during walking/exercise. This subjects the muscles to repeated ischemia and reperfusion injury that can alter structure and oxidative metabolism, resulting in insufficient utilization of oxygen supply. Despite extensive research efforts, cilostazol and pentoxifylline are the only drugs indicated for relieving the symptoms of IC, with cilostazol demonstrating significant improvement in walking distance and quality of life in these patients. Originally developed as a PDE3 inhibitor, cilostazol was later found to have several other pharmacological actions, and its success has been attributed to its multifactorial actions on platelets, endothelium, smooth muscle, and lipid profiles. Using cilostazol as an example, we discuss the rationales and pitfalls of targeting PDEs in IC, and potential strategies for the development of new and more effective pharmacological treatments.

Phosphodiesterases as targets for intermittent claudication.

NT-702 (parogrelil hydrochloride, NM-702), a novel and potent phosphodiesterase inhibitor, improves reduced walking distance and lowered hindlimb plantar surface temperature in a rat experimental intermittent claudication model.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Yusuke Ito

Author Tools

Chat about Author

Papers

NT-702 (parogrelil hydrochloride, NM-702), a novel and potent phosphodiesterase inhibitor, improves reduced walking distance and lowered hindlimb plantar surface temperature in a rat experimental intermittent claudication model.