scholarly journals New Small Molecule Drugs for Thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations

2019 ◽  
Vol 20 (12) ◽  
pp. 3013 ◽  
Author(s):  
Page Clemons Bankston ◽  
Rami A. Al-Horani
Keyword(s):  
Small Molecules ◽  
Previous Treatment ◽  
Specific Patient ◽  
Chemical Structures ◽  
Small Molecule Drugs ◽  
Thrombopoietin Receptor ◽  
Insufficient Response ◽  
Syk Inhibitor ◽  
New Treatments ◽  
Orally Active

This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.

scholarly journals Nano-chemistry and Bio-conjugation with perspectives on the design of Nano-Immune platforms, vaccines and new combinatorial treatments

2021 ◽  
pp. 049-056
Author(s):  
Gomez Palacios Luna R ◽  
Martinez Sofia ◽  
Tettamanti Cecilia ◽  
Quinteros Daniela ◽  
Bracamonte A Guillermo
Keyword(s):  
Small Molecules ◽  
Mechanisms Of Action ◽  
Chemical Structures ◽  
Functional Nanoparticles ◽  
Corona Virus ◽  
New Treatments

This Mini-Review and Opinion letter, it was addressed different themes and topics implicated in the development of new treatments and vaccines applied to pathologies developed in humans such as by Virus and related pathogens. In this context, it was presented and discussed different strategies used, which were contemplated from the design of small molecules, towards higher sized chemical structures and new Nanoarchitectures. In particular, it was discussed varied studies developed for the Corona Virus treatment; which afforded to the main mechanisms of action of pharmacophores and targeted functional Nanoparticles. In this direction, it was highlighted the importance of Bioconjugation of molecules and variable Nanoarchitectures for their incorporation within cells as well as for the development of Nano-vaccines. Moreover, it was discussed about the development of combinatory treatments based on different strategies recently reported. Similarly, it was presented different studies and developments actually in progress related to the design of functional and Multifunctional Nano-platforms with potential perspectives on Lab-On particles and Nano-vaccines for precision Nanomedicine and new treatments.

scholarly journals Transitioning From Thrombopoietin Agonists to the Novel SYK Inhibitor Fostamatinib: A Multicenter, Real-World Case Series

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
David M. Hughes, PharmD, BCOP ◽  
Charina Toste, DNP, APN ◽  
Christopher Nelson, ACNP-BC ◽  
Juliet Escalon, ANP ◽  
Frances Blevins, PA-C ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adverse Events ◽  
Real World ◽  
Rescue Therapy ◽  
Case Series ◽  
Previous Treatment ◽  
Safety And Efficacy ◽  
Insufficient Response ◽  
Syk Inhibitor ◽  
Favorable Clinical Outcome

Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor used for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Clinical and operational barriers may exist that warrant bridging or switching from thrombopoietin receptor agonists (TPO-RAs), such as volatility or unpredictability of platelets, adverse events, and quality of life or patient preference. While fostamatinib demonstrated durable platelet responses, the safety and efficacy in combination, bridging, and/or switching with TPO-RAs is not well documented. The objective of this article is to provide guidance from real-world case studies for a safe and effective strategy for the transitioning of patients from TPO-RAs to fostamatinib, with some degree of overlap between the two agents. Currently, the evidence does not exist to guide the safe and effective use of combination therapy or transition between therapies in ITP. This case series highlights the importance to further understand the complexities of managing this disease, as well as successfully combining, bridging, and/or switching patients over to fostamatinib without the need for rescue therapy or increase in adverse events. The need for real-world evidence that guides providers on the safety and efficacy of short- and long-term combination therapy of fostamatinib and TPO-RAs is crucial. The rationale for combination therapy is to target different pathways, platelet destruction, and production without added toxicities. Additionally, gradual tapering off of TPO-RAs may provide a more favorable clinical outcome when switching to fostamatinib. The need for additional data is necessary to provide clinicians with guidance when managing patients with ITP.

scholarly journals BIOSIMILARS IN INFLAMMATORY BOWEL DISEASES: an important moment for Brazilian gastroenterologists

2015 ◽  
Vol 52 (1) ◽  
pp. 76-80 ◽  
Author(s):  
Fábio Vieira TEIXEIRA ◽  
Paulo Gustavo KOTZE ◽  
Aderson Omar Mourão Cintra DAMIÃO ◽  
Sender Jankiel MISZPUTEN
Keyword(s):  
Small Molecules ◽  
Inflammatory Bowel Diseases ◽  
Generic Drugs ◽  
Specific Data ◽  
Chemical Structures ◽  
Bowel Diseases ◽  
Original Product ◽  
Inflammatory Bowel ◽  
The One ◽  
Extrapolation Of Indications

ABSTRACT Biosimilars are not generic drugs. These are more complex medications than small molecules, with identical chemical structures of monoclonal antibodies that lost their patency over time. Besides identical to the original product at the end, the process of achieving its final forms differs from the one used in the reference products. These differences in the formulation process can alter final outcomes such as safety and efficacy of the drugs. Recently, a biosimilar of Infliximab was approved in some countries, even to the management of inflammatory bowel diseases. However, this decision was based on studies performed in rheumatologic conditions such as rheumatoid arthritis and ankylosing spondylitis. Extrapolation of the indications from rheumatologic conditions was done for Crohn’s disease and ulcerative colitis based on these studies. In this article, the authors explain possible different mechanisms in the pathogenesis between rheumatologic conditions and inflammatory bowel diseases, that can lead to different actions of the medications in different diseases. The authors also alert the gastroenterological community for the problem of extrapolation of indications, and explain in full details the reasons for being care with the use of biosimilars in inflammatory bowel diseases without specific data from trials performed in this scenario.

GLAXO/MRS PAPERRoles of chemokines in the regulation of leucocyte recruitment*

2001 ◽  
Vol 100 (4) ◽  
pp. 359-362
Author(s):  
Ian SABROE ◽  
Timothy J. WILLIAMS ◽  
James E. PEASE
Keyword(s):  
Small Molecules ◽  
Inflammatory Disease ◽  
Chemokine Receptors ◽  
Allergic Inflammation ◽  
New Treatments ◽  
Leucocyte Recruitment

In the search for new treatments for human inflammatory disease, antagonism of chemokine receptors by small molecules is an attractive goal. Although there are overlapping patterns of expression of chemokine receptors between leucocyte types, an investigation of the chemokine responsiveness of cells important in allergic inflammation, such as the eosinophil and the basophil, is beginning to uncover how selective recruitment may be regulated. The story of the eotaxin receptor, CCR3, and its central role in allergic inflammation illustrates that therapeutic antagonism of these pathways is imminently achievable.

Small Molecules as PD-1/PD-L1 Pathway Modulators for Cancer Immunotherapy

2019 ◽  
Vol 24 (41) ◽  
pp. 4911-4920 ◽  
Author(s):  
Peifu Jiao ◽  
Qiaohong Geng ◽  
Peng Jin ◽  
Gaoxing Su ◽  
Houyun Teng ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Immunotherapy ◽  
Therapeutic Antibodies ◽  
Manufacturing Costs ◽  
Tumor Penetration ◽  
Chemical Structures ◽  
Structure Activity ◽  
Cancer Models ◽  
Alternative Approach ◽  
Intracellular Targets

Blockade of PD-1/PD-L1 interactions using PD-1/PD-L1 pathway modulators has shown unprecedented clinical efficacy in various cancer models. Current PD-1/PD-L1 modulators approved by FDA are exclusively dominated by therapeutic antibodies. Nevertheless, therapeutic antibodies also exhibit several disadvantages such as low tumor penetration, difficulty in crossing physiological barriers, lacking oral bioavailability, high manufacturing costs, inaccessible to intracellular targets, immunogenicity, immune-related adverse events (irAEs). Modulation of PD-1/PD-L1 pathway using small molecules may be an alternative approach to mobilize immune system to fight against cancers. In this review, we focus on summarizing the recently disclosed chemical structures and preliminary structure-activity relationships (SARs) of small molecules as PD-1/PD-L1 modulators for cancer immunotherapy.

scholarly journals Recent Advances in One-Pot Modular Synthesis of 2-Quinolones

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5450
Author(s):  
Wan Pyo Hong ◽  
Inji Shin ◽  
Hee Nam Lim
Keyword(s):  
Reaction Mechanism ◽  
Small Molecules ◽  
Functional Materials ◽  
Synthetic Methods ◽  
Microwave Irradiation Method ◽  
One Pot ◽  
Bond Forming ◽  
Chemical Structures ◽  
The Core ◽  
Modular Synthesis

It is known that 2-quinolones are broadly applicable chemical structures in medicinal and agrochemical research as well as various functional materials. A number of current publications about their synthesis and their applications emphasize the importance of these small molecules. The early synthetic chemistry originated from the same principle of the classical Friedländer and Knorr procedures for the preparation of quinolines. The analogous processes were developed by applying new synthetic tools such as novel catalysts, the microwave irradiation method, etc., whereas recent innovations in new bond forming reactions have allowed for novel strategies to construct the core structures of 2-quinolones beyond the bond disconnections based on two classical reactions. Over the last few decades, some reviews on structure-based, catalyst-based, and bioactivity-based studies have been released. In this focused review, we extensively surveyed recent examples of one-pot reactions, particularly in view of modular approaches. Thus, the contents are categorized as three major sections (two-, three-, and four-component reactions) according to the number of reagents that ultimately compose atoms of the core structures of 2-quinolones. The collected synthetic methods are discussed from the perspectives of strategy, efficiency, selectivity, and reaction mechanism.

scholarly journals Susceptibility of protein therapeutics to spontaneous chemical modifications by oxidation, cyclization, and elimination reactions

Amino Acids ◽  
2019 ◽  
Vol 51 (10-12) ◽  
pp. 1409-1431 ◽  
Author(s):  
Luigi Grassi ◽  
Chiara Cabrele
Keyword(s):  
Small Molecules ◽  
Three Dimensional ◽  
Drug Market ◽  
Structure And Function ◽  
Dimensional Structure ◽  
Chemical Modifications ◽  
Small Molecule Drugs ◽  
And Function ◽  
The Impact

Abstract Peptides and proteins are preponderantly emerging in the drug market, as shown by the increasing number of biopharmaceutics already approved or under development. Biomolecules like recombinant monoclonal antibodies have high therapeutic efficacy and offer a valuable alternative to small-molecule drugs. However, due to their complex three-dimensional structure and the presence of many functional groups, the occurrence of spontaneous conformational and chemical changes is much higher for peptides and proteins than for small molecules. The characterization of biotherapeutics with modern and sophisticated analytical methods has revealed the presence of contaminants that mainly arise from oxidation- and elimination-prone amino-acid side chains. This review focuses on protein chemical modifications that may take place during storage due to (1) oxidation (methionine, cysteine, histidine, tyrosine, tryptophan, and phenylalanine), (2) intra- and inter-residue cyclization (aspartic and glutamic acid, asparagine, glutamine, N-terminal dipeptidyl motifs), and (3) β-elimination (serine, threonine, cysteine, cystine) reactions. It also includes some examples of the impact of such modifications on protein structure and function.

Fragment-based drug design of nature-inspired compounds

2019 ◽  
Vol 4 (9) ◽  
Author(s):  
Abdulkarim Najjar ◽  
Abdurrahman Olğaç ◽  
Fidele Ntie-Kang ◽  
Wolfgang Sippl
Keyword(s):  
Drug Design ◽  
Small Molecules ◽  
Small Molecule ◽  
Binding Pocket ◽  
Biological Macromolecules ◽  
Drug Candidates ◽  
Fragment Screening ◽  
Small Molecule Drugs ◽  
Lead Generation ◽  
Hit Identification

Abstract Natural product (NP)-derived drugs can be extracts, biological macromolecules, or purified small molecule substances. Small molecule drugs can be originally purified from NPs, can represent semisynthetic molecules, natural fragments containing small molecules, or are fully synthetic molecules that mimic natural compounds. New semisynthetic NP-like drugs are entering the pharmaceutical market almost every year and reveal growing interests in the application of fragment-based approaches for NPs. Thus, several NP databases were constructed to be implemented in the fragment-based drug design (FBDD) workflows. FBDD has been established previously as an approach for hit identification and lead generation. Several biophysical and computational methods are used for fragment screening to identify potential hits. Once the fragments within the binding pocket of the protein are identified, they can be grown, linked, or merged to design more active compounds. This work discusses applications of NPs and NP scaffolds to FBDD. Moreover, it briefly reviews NP databases containing fragments and reports on case studies where the approach has been successfully applied for the design of antimalarial and anticancer drug candidates.

scholarly journals Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
James O’Connell ◽  
John Porter ◽  
Boris Kroeplien ◽  
Tim Norman ◽  
Stephen Rapecki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
General Mechanism ◽  
Protein Protein Interactions ◽  
Biologic Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53–MDM2 Interaction and the NF-κB Pathway

2014 ◽  
Vol 57 (3) ◽  
pp. 567-577 ◽  
Author(s):  
Chunlin Zhuang ◽  
Zhenyuan Miao ◽  
Yuelin Wu ◽  
Zizhao Guo ◽  
Jin Li ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Therapeutics ◽  
Orally Active
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