1,721,039 research outputs found
Synthesis, biological activity and SARs of new heteroaryl-substituted isonipecotanilide inhibitors of the blood coagulation factors
No full textNovel factor Xa inhibitors: a patent review
No full textIMPORTANCE OF THE FIELD:
New oral anticoagulants with favorable safety profiles and fixed doses are required for the management of thromboembolism and stroke prevention in patients with atrial fibrillation. Among them, fXa inhibitors (the so-called xabans) are attractive options that can overcome limitations (e.g., bleeding) of the current oral antithrombotic therapy. The rational design of small-molecule direct fXa inhibitors, whose importance is testified by the growing number of publications and patents recently registered, has been fully supported by the X-ray crystallography of enzyme-ligand complexes.
AREAS COVERED IN THIS REVIEW:
Pubmed, SciFinder Scholar, ISI web of knowledge(SM), http://ep.espacenet.com/ and Google websites were used as the main sources for literature retrieving, and > 100 patents filed between 2006 and April 2009, reviewed and discussed herein, highlight the variety among the P1 and P4 moieties on suitable scaffolds.
WHAT THE READER WILL GAIN:
The replacement of the benzamidine P1 moiety, which characterizes the first generation, with less basic bioisosteric or nonpolar neutral P1 groups led to the disclosure of numerous fXa inhibitors with high potency, selectivity and oral bioavailability. Novel selective fXa inhibitors with stable pharmacokinetics, better therapeutic windows and ease-of-use than the existing anticoagulants are currently under advanced stage clinical trials.
TAKE-HOME MESSAGE:
Available data from Phase II and Phase III studies reflect the drive towards fXa inhibitors as potentially more effective and safer antithrombotic drugs. Their development is expected to address two major needs for anticoagulation, namely safety and ease-of-use, and to significantly affect the anticoagulant market
New azepino[4,3-b]indole derivatives, as selective butyrylcholinesterase inhibitors with potential for neurodegenerative disorders
No full textStarting from the cholinergic hypothesis, which originally implied a major role of acetylcholinesterase (AChE) in the cognitive impairment of the Alzheimer’s disease (AD), the role of butyrylcholinesterase (BChE) has progressively become more crucial in the AD development and progression. Indeed, it has been shown that the levels of AChE in the AD brain decrease by as much as 90%, whilst the levels of BChE, mainly in the G1 form (i.e., globular form of monomer structure), increase, suggesting that inhibition of BChE may represent a privileged target to develop new drugs for treating neurodegenerative diseases. As a matter of fact, in the last years several efforts have been made to identify selective BChE inhibitors, such as tricyclic cymserine analogs, which proved beneficial in vivo in animal models, most likely by recovering cholinergic activity and/or by restoring AChE:BChE activity ratios to the levels observed in the healthy brain.
Previously, we reported the ChE inhibition activity of novel medium-sized nitrogen-containing heterocycles (e.g., tetrahydroazocines) fused on indole, which showed ChE inhibition activity. Herein, we explore the ChE inhibition activity of a series of 3,4,5,6-tetrahydroazepino[4,3-b]indole derivatives, some of which proved to be highly potent and selective BChE inhibitors, with low toxicity as assessed in vitro on neuroblastoma cell cultures. Among the newly synthesized compounds, the lactam derivative 2 showed the highest BChE inhibition potency (IC50 = 1.5 nM), whereas further investigation showed that the above tricyclic system could provide a promising scaffold for new multimodal derivatives with potential in the treatment of neurodegenerative disorders
Organofluorine-containing therapeutics for treatment of cardiovascular disease
No full textA number of organofluorine-containing drugs for prevention and treatment of cardiovascular disease have been launched worldwide over the past 50 years, with 40% of them being approved in the last decade; they belong to the categories of cholesterol-lowering agents (especially statins), antiarrhythmics, calcium-channel blockers for treating high blood pressure and chest pain (angina), thiazide diuretics used in treating hypertension and congestive heart failure, and antiplatelet agents for use in post-heart attack and valve replacement
Fluorinated benzyloxyphenyl piperidine-4-carboxamides with dual function against thrombosis: Inhibitors of factor Xa and platelet aggregation
No full textA series of benzyloxy anilides of nipecotic (5, 6) and isonipecotic (7, 8) acids were synthesized and assayed in vitro as inhibitors of ADP-induced platelet aggregation and the blood coagulation enzymes factor Xa (FXa) and thrombin (FIIa). An exploration of effects of the amidine group attached at the piperidine nitrogen, position and substitution (F, phenyl) of the benzyloxy group, and addition of fluorine/s on the second (distal) phenyl ring, led us to single out some promising isonipecotamide derivatives 7. Addition of meta-F and para-CF(3) on the distal phenyl ring resulted in a 6-to-18-fold enhancement of the FXa potency and in 2-to-4-fold increase of the antiplatelet potency, the last depending to a large extent upon lipophilicity. Two congeners of N-{[3-(1,1'-biphenyl-4-yl)methoxy]phenyl}piperidine-4-carboxamide (7m and 7p) proved to be potent FXa-selective inhibitors (K(i) = 130 and 57 nM, respectively) and antiplatelet agents and were identified as leads for developing new dual function antithrombotic drugs
The exploration of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole derivatives as selective butyrylcholinesterase inhibitors
No full textThe role of butyrylcholinesterase (BChE) in the progression of Alzheimer’s disease (AD) has recently become more crucial (1). It is known that in healthy human brain acetylcholinesterase (AChE) predominates over BChE activity, but, as AD progresses, The levels of AChE in the brain decrease by as much as 90%, whilst the levels of BChE, Mainly in the G1 form (i.e., globular form of monomer structure), increase (2,3). This suggests that the inhibition of BChE may be useful in ameliorating the cholinergic
transmission, which likely worsen in AD due to the BChE increased activity (4). As a matter of fact, in the AD brain, selective BChE inhibitors, such as tricyclic cymserine Analogs (1,5), have been demonstrated to have beneficial effects in vivo, probably by recovering cholinergic activity and/or by restoring AChE:BChE activity ratios to the levels observed in the healthy brain. Some years ago, we reported the ChE inhibition activity of novel annulated (e.g., pyrrole- and indole-fused) tetrahydroazocines, which showed AChE selectivity (6). Herein, we explore the ChE inhibition activity of a large series of 1,2,3,4,5,6-hexahydroazepino[4,3-b]ndole
derivatives, some of which proved to be potent and selective BChE inhibitors. In particular, the lactam
derivative 2 was highly active against BChE, with a subnanomolar IC50 Value. Synthesis, enzyme inhibition
data and SARs are presented and discussed
A second life for MAO inhibitors? From CNS diseases to anticancer therapy
Full text linkMonoamine oxidases A and B (MAO A, B) are ubiquitous enzymes responsible for oxidative deamination of amine neurotransmitters and xenobiotics. Despite decades of studies, MAO inhibitors (MAOIs) find today limited therapeutic space as second-line drugs for the treatment of depression and Parkinson's disease. In recent years, a renewed interest in MAOIs has been raised up by several studies investigating the role of MAOs, particularly MAO A, in tumor insurgence and progression, and the efficacy of MAOIs as coadjutants in the therapy of chemoresistant tumors. In this survey, we highlight the implication of MAOs in the biochemical pathways of tumorigenesis and review the state-of-the-art of preclinical and clinical studies of MAOIs as anticancer agents used in monotherapy or in combination with antitumor chemotherapeutics
Pyridone-Hydroxypyridine Tautomerism as Encoded into Lipophilicity parameters of cardiotonic Milrinone Analogs
No full textProbing new inhibitors of platelet aggregation showing additional antithrombotic activities
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