1,721,031 research outputs found
Biologically driven synthesis of pyrazolo[3,4-d]pyrimidines as protein kinase inhibitors: an old scaffold as a new tool for medicinal chemistry and chemical biology studies
No full textNitrogen-containing heterocycles are widely distributed in
nature and essential for life, playing a vital role in the
metabolism of all living cells. Among the many nitrogencontaining
heterocycles, the pyrazolo[3,4-d]pyrimidine nucleus
(Figure 1) is an important drug-like scaffold that is present in
many pharmacologically active compounds. This review describes the synthesis of pyrazolo-pyrimidines and their activities as kinase inhibitors
Analogs, formulations and derivatives of imatinib: A patent review
No full textThe Bcr-Abl inhibitor imatinib was approved in 2001 for chronic myeloid leukemia therapy, and dramatically changed the lives of patients affected by this disease. Since it also inhibits platelet derived growth factor receptor (PDGFR) and c-Kit, imatinib is used for various other tumors caused by abnormalities of one or both these two enzymes. This review presents an overview on imatinib formulations and derivs., synthetic methodologies and therapeutic uses that have appeared in the patent literature since 2008. Innovative imatinib formulations, such as nanoparticles contg. the drug, will improve its bioavailability. Moreover, oral solns. or high imatinib content tablets or capsules will improve patient compliance. Some solid formulations and innovative syntheses that have appeared in the last few years will reduce the cost of the drug, offering big advantages for poor countries. Some recently patented efficacious imatinib derivs. are in preclin. studies and could enter clin. trials in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further
A1 receptors ligands: past, present and future trends.
No full textAdenosine is a neuromodulator that interacting with four receptors, A(1), A(2A), A(2B) and A(3), is involved in the regulation of several biological functions in different organs and tissues, including the central nervous system, the cardiovascular system and the airways; many pathophysiological states are associated with changes of adenosine levels. For these reasons pharmaceutical companies and academicians performed intense efforts to obtain agonists, antagonists and allosteric enhancers selective for each adenosine receptor subtypes as potential clinical candidates. In fact, therapeutic modulation of the adenosine system could offer the possibility of a "soft" treatment of different diseases, but, due to the ubiquitous distribution of adenosine and of its receptors, the challenge in therapy development depends from specificity for the different receptor subtypes. Some A(1) agonists and antagonists, very potent and selective, reached clinical trials for the treatment of different diseases. A(1) agonists are clinical candidates for atrial arrhythmias, angina, type 2 diabetes and in pain management, while A(1) antagonists are in study as potassium-sparing diuretics with kidney-protecting properties and in chronic heart diseases. Several reviews, recently published and herein cited reported in detail the biological and clinical aspects of such molecules. This review focuses on the A(1) adenosine receptor (A(1)AR) ligands, both agonists and antagonists, appeared in the literature in the last few years, together with their potential therapeutic application, pointing the attention on their chemical structures and SAR (Structure Activity Relationship) and also reporting new findings on preclinical or clinical trials of some important A(1)AR ligands synthesized in the past
Synthesis of pyrazolo[3,4-d]pyrimidine derivatives endowed with activity against the T315I Abl mutation
No full textATP-competitive inhibitors of mTOR: an update.
No full textmTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway
that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been
detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR
exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents.
Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a
number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete
anticancer activity in comparison with that of rapamycin and its derivatives.
mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signalling
pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by
preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced
therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents.
This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their
chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD-
8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of
dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and
clinical data
Bcr-Abl tyrosine kinase inhibitors: A patent review
No full textBreakpoint cluster region Abelson (Bcr-Abl) tyrosine kinase (TK) is a constitutively activated cytoplasmic TK and is the underlying cause of chronic myeloid leukemia (CML). To date, imatinib represents the frontline treatment for CML therapy. The development of resistance has prompted the search for novel Bcr-Abl inhibitors. Areas covered: This review presents a short overview of drugs already approved for CML therapy and of the compds. that are in clin. trials. The body of the article deals with Bcr-Abl inhibitors patented since 2008, focusing on their chem. features. Expert opinion: The search for Bcr-Abl inhibitors is very active. We believe that a no. of patented compds. could enter clin. trials and some could be approved for CML therapy in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further
Synthesis of pyrazolo[3,4-d]pyrimidine derivatives active against the T315I Abl mutation.
No full textNovel dual Src/Abl inhibitors for hematologic and solid malignancies.
No full textA review. C-Src and Bcr-Abl are 2 non-receptor or cytoplasmic tyrosine kinases (TKs) that play important roles in the development of solid and hematol. malignancies. Indeed, Src is overexpressed or hyperactivated in a variety of solid tumors, while Bcr-Abl is the causative agent of chronic myeloid leukemia (CML), where Src is also involved. The 2 enzymes share significant sequence homol. and remarkable structural resemblance. ATP-competitive compds. originally developed as Src inhibitors, showed to be also potent Abl inhibitors. Dasatinib, the first dual Src/Abl inhibitor approved by the US FDA in 2006 for the treatment of imatinib-resistant CML, is currently being tested in several clin. trials for the treatment of different solid tumors. SKI-606 and AZD0530 are 2 other important dual Src/Abl inhibitors extensively tested in animal models and in clin. trials, but not entered into therapy yet. In this review we will report the latest results regarding dasatinib, SKI-606 and AZD0530, but also the knowledge on new compds. that have appeared in the literature in the last few years, including AP24163, AP24534, XL228, DC2036. We will focus on the most recent clin. trials or on preclin. studies that are in progress on these small-mol. TK inhibitors that represent a targeted therapy with high potential against cancer. Molecularly targeted therapies, including the inhibition of specific TKs hyperactivated or overexpressed in many human cancers, could be less toxic than the classical non-specific cytotoxic chemotherapeutic agents; they could offer important therapeutic effects, esp. if used in assocn. with other agents such as monoclonal antibodies
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