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1.
Curr Med Chem ; 19(20): 3353-87, 2012.
Article in English | MEDLINE | ID: mdl-22680630

ABSTRACT

The clinical treatment of multifactorial pathologies (e.g. cancer, Alzheimer's disease, psychiatric disorders), is still a major challenge. Many researches have been published dealing with the design of multiple ligands, able to act at the same time towards several targets relevant for a given pathology. In the present review, the clinical results about these compounds have been reported, together with the design strategy adopted, in order to allow a critical evaluation of the outcomes of these efforts. What is emerging is that several effective design strategies of multitarget compounds are available, and the choice among these appears to be dependent on the therapeutic area considered. However, at present, besides multitarget drugs discovered during optimization efforts by means of phenotypic assays, drug coadministrations or fixed dose formulations appear to be more useful therapeutic options than designed multiple ligands; this scenario will change when systems biology will be able to select critical targets, i.e. nodal proteins that should be inhibited in order to obtain a therapeutic action; at this point, the design of multiple ligands will allow a renaissance of medicinal chemistry.


Subject(s)
Drug Design , Molecular Targeted Therapy/methods , Research , Animals , Humans , Ligands
2.
Curr Med Chem ; 15(18): 1827-39, 2008.
Article in English | MEDLINE | ID: mdl-18691041

ABSTRACT

SSAO/VAP-1 is not only involved in the metabolism of biogenic and xenobiotic primary amines and in the production of metabolites with cytotoxic effects or certain physiological actions, but also plays a role, for example, as an adhesion molecule, in leukocyte trafficking, in regulating glucose uptake and in adipocyte homeostasis. Interest in the enzyme has been stimulated by the findings that the activities of the SSAOs are altered (mostly increased) in various human disorders, including diabetes, congestive heart failure, liver cirrhosis, Alzheimer's disease and several inflammatory diseases, although the underlying causes are often unknown. On the basis of their insulin-mimicking effect, SSAO substrates are possibly capable of ameliorating metabolic changes in diabetes, while SSAO inhibitors (somewhat of a contradiction) are of potential benefit in preventing diabetes complications, atherosclerosis and oxidative stress contributing to several disorders or modulating inflammation, and hence may be of substantial therapeutic value. Great efforts have been made to develop novel compounds which may lead to future drugs useful in therapy, based on their effects on SSAO/VAP-1, and some of the results relating to novel substrates and inhibitors are surveyed in the present review.


Subject(s)
Amine Oxidase (Copper-Containing)/antagonists & inhibitors , Amine Oxidase (Copper-Containing)/chemistry , Monoamine Oxidase/chemistry , Semicarbazides/chemistry , Alzheimer Disease/drug therapy , Amine Oxidase (Copper-Containing)/metabolism , Amines/chemistry , Animals , Blood/metabolism , Cattle , Cell Adhesion Molecules/metabolism , Diabetes Mellitus/drug therapy , Humans , Inhibitory Concentration 50 , Plasma/metabolism , Rats , Substrate Specificity
3.
Curr Med Chem ; 12(19): 2241-58, 2005.
Article in English | MEDLINE | ID: mdl-16178783

ABSTRACT

Recent methodologies applied to the drug discovery process, such as genomics and proteomics, have greatly implemented our basic understanding of drug action and are giving more input to medicinal chemists, in finding genuinely new targets and opportunities for the development of drugs with original mechanisms of action. In this paper, an example of the successful application of some new techniques to the target enzymes with the Thymidylate Synthase (TS) function is given. The improved knowledge of the complex mechanism of the biological pathways in which thymidylate synthase is involved represents a unique chance to find new mechanism-based inhibitors, aimed to treat not only cancerous diseases, but also infectious pathologies. Thymidylate synthase (TS or ThyA) has long been considered as one of the best-known drug targets in the anti-cancer area, after which old and new drugs, such as 5-fluoro uracil and the anti-folate ZD1694, have been introduced into chemotherapy to treat solid tumours. Only a few attempts have been made to find non-classical anti-folate inhibitors that are dissimilar to the folate co-factor, with the aim of finding unshared protein target domains on the enzyme structure, in order to specifically inhibit TS enzymes from pathogens. Only recently from omic studies, a new Thymidylate Synthase Complementing Protein (TSCP or ThyX) has been identified in a number of pathogens, showing a different structure with respect to human TS, thus opening new avenues to specific inhibitions. A depiction of the most recent progress in the study of Thymidylate Synthase enzymes is presented in the following sections.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Folic Acid Antagonists/pharmacology , Thymidylate Synthase/metabolism , Antineoplastic Agents/therapeutic use , Drug Design , Enzyme Inhibitors/therapeutic use , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Folic Acid Antagonists/therapeutic use , Humans , Molecular Sequence Data , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sequence Alignment , Structure-Activity Relationship , Thymidylate Synthase/antagonists & inhibitors , Thymidylate Synthase/chemistry
4.
Curr Med Chem ; 11(10): 1285-98, 2004 May.
Article in English | MEDLINE | ID: mdl-15134520

ABSTRACT

Semicarbazide-sensitive amine-oxidase (SSAO) is present in various human tissues and in plasma. Oxidative deamination of short-chain aliphatic amines is catalyzed by this enzyme to afford the corresponding aldehydes, ammonia and hydrogen peroxide. Methylamine and aminoacetone have been recognized to be physiological substrates for SSAO. There are several pathological states where increased serum SSAO activity have been found, such as diabetes mellitus, congestive heart failure, multiple types of cerebral infarction, uraemia, and hepatic cirrhosis. The role of SSAO in pathophysiology of diabetes has been most extensively investigated. The elevated formation of the potentially cytotoxic products of the enzyme may contribute to the endothelial injury of blood vessels, resulting in the early development of severe atherosclerosis; it may also contribute to the pathogenesis of diabetic angiopathy. It is now suggested that SSAO inhibitors may prevent the development of atherosclerosis and diabetic complications as well. Inhibitors can be conveniently subdivided into the main groups of hydrazine derivatives, arylalkylamines, propenyl- and propargylamines, oxazolidinones, and haloalkylamines. Of them, aryl(alkyl)hydrazines, and 3-halo-2-phenylallylamines are generally very strong SSAO inhibitors. Most of these inhibitors of SSAO have been originally developed for other purposes, or they are simple chemical reagents with highly reactive structural element(s); these compounds have not been able to fulfil all criteria of high potency, selectivity, and acceptable toxicity. New potent compounds with selectivity and low toxicity are needed, which may prove useful tools for understanding the roles and function of SSAO, or they may even be valuable substances for treatment of various diseases.


Subject(s)
Amine Oxidase (Copper-Containing) , Amine Oxidase (Copper-Containing)/antagonists & inhibitors , Amine Oxidase (Copper-Containing)/blood , Amine Oxidase (Copper-Containing)/physiology , Arteriosclerosis/drug therapy , Arteriosclerosis/prevention & control , Blood Vessels/drug effects , Diabetes Mellitus/drug therapy , Diabetes Mellitus/enzymology , Diabetes Mellitus/prevention & control , Enzyme Inhibitors/therapeutic use , Humans , Molecular Structure
5.
Mini Rev Med Chem ; 3(6): 576-84, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12871160

ABSTRACT

Inhibition of ACAT, the enzyme which catalyses the intracellular formation of cholesteryl esters, is a very attractive target for the treatment of hypercholesterolaemia and atherosclerosis. However, in the past years many ACAT inhibitors gave disappointing results in clinical trials showing very low efficacy. In addition, their development was affected by the adrenotoxicity observed in many compounds. The discovery of two isoforms of the enzyme, namely ACAT1 and ACAT2, with different substrate specificity and different potential function, offers a precious information for planning selective inhibitors with reduced secondary effects. Today some potent, bioavailable and non adrenotoxic ACAT inhibitors are under clinical evaluation. Amongst others, a very promising compound is Avasimibe, presently in phase III clinical trials as anti-hyperlipidemic and anti-atherosclerotic agent. Finally, ACAT inhibitors have recently been proposed for the treatment of Alzheimer's disease.


Subject(s)
Enzyme Inhibitors/pharmacology , Hypolipidemic Agents/pharmacology , Sterol O-Acyltransferase/antagonists & inhibitors , Alzheimer Disease/drug therapy , Arteriosclerosis/drug therapy , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Hyperlipidemias/drug therapy , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/therapeutic use , Sterol O-Acyltransferase/metabolism
6.
Pharmazie ; 58(2): 140-2, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12641333

ABSTRACT

Tecostanine (1) was isolated from Tecoma stans leaves. Its sterochemistry was elucidated as well as its antihyperglycemic activity and its affinity to opioid and nicotinic receptors. The oxalate salt of 1 did not significantly affect blood glucose levels in normoglycaemic and hyperglycaemic rats. It did not appear to interact with opioid receptors (mu type) and showed only moderate affinity to the nicotinic receptor.


Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Bignoniaceae/chemistry , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Plants, Medicinal/chemistry , Terpenes/chemistry , Terpenes/pharmacology , Animals , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Male , Mexico , Models, Molecular , Molecular Conformation , Rats , Rats, Sprague-Dawley , Receptors, Nicotinic/drug effects , Receptors, Opioid/drug effects
7.
J Med Chem ; 44(24): 4292-5, 2001 Nov 22.
Article in English | MEDLINE | ID: mdl-11708931

ABSTRACT

Alkyl-5,6-diphenylpyridazine derivatives combining several main features of ACAT inhibitors, such as a long alkyl side chain linked to a heterocycle and the o-diphenyl system, were synthesized and tested. Moreover, modeling studies on representative terms were performed. Some compounds displayed ACAT inhibition in the micromolar range, both on the enzyme isolated from rat liver microsomes and in cell-free homogenate of murine macrophages.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Pyridazines/chemical synthesis , Sterol O-Acyltransferase/antagonists & inhibitors , Animals , Cell-Free System , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , In Vitro Techniques , Macrophages/drug effects , Macrophages/enzymology , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Models, Molecular , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Structure-Activity Relationship
8.
Drug Discov Today ; 6(20): 1068-1071, 2001 Oct 15.
Article in English | MEDLINE | ID: mdl-11590036
9.
Drug Discov Today ; 6(18): 962-964, 2001 Sep 15.
Article in English | MEDLINE | ID: mdl-11546611
10.
Curr Opin Investig Drugs ; 2(5): 650-3, 2001 May.
Article in English | MEDLINE | ID: mdl-11569941

ABSTRACT

Calyx Therapeutics is developing the insulin sensitizer, CLX-0901, as an antidiabetic agent. CLX-0901 is the synthetic analog of CLX-0900 which was originally isolated from a plant source. Phase I and toxicological studies indicate that the compound is safe and well tolerated [363764]. As of March 2001, phase II studies had commenced [402737]. Other antidiabetics being investigated by Calyx include CLX-0301, CLX-0921, CLX-0940, CLX-0100 and CLX-0101 [376032].


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/pharmacology , Stilbenes/pharmacology , Animals , Clinical Trials as Topic , Contraindications , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/toxicity , Insulin Resistance , Stilbenes/pharmacokinetics , Stilbenes/therapeutic use , Stilbenes/toxicity , Structure-Activity Relationship
11.
Drug Discov Today ; 6(19): 1025-1028, 2001 Oct 01.
Article in English | MEDLINE | ID: mdl-11576868
12.
Drug Discov Today ; 6(16): 859, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11495760

ABSTRACT

Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.

13.
Drug Discov Today ; 6(17): 915-916, 2001 Sep 01.
Article in English | MEDLINE | ID: mdl-11522520
14.
Eur J Med Chem ; 36(6): 495-506, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11525840

ABSTRACT

Ambasilide, a representative of Class III antiarrhythmics, was reported to prolong the cardiac action potential duration in the dog, with little or no effect on Ca and Na currents. We synthesised a series of ambasilide analogues, having the 3,8-diazabicyclo-[3.2.1]-octane moiety instead of the 3,7-diazabicyclo-[3.3.1]-nonane present in ambasilide. The compounds were tested both in vitro extracellular electrophysiological assays and by the conventional microelectrode technique. Most of them lengthened the effective refractory period (ERP) with no change or slight increase on the impulse conduction time (ICT). Similarly some of the tested compounds lengthened the action potential duration (APD), a typical Class III feature, without exerting any significant effect on the maximal rate of depolarization, therefore apparently lacking Class I antiarrhythmic activity.


Subject(s)
Aminobenzoates/chemistry , Aminobenzoates/pharmacology , Anti-Arrhythmia Agents/chemistry , Anti-Arrhythmia Agents/chemical synthesis , Anti-Arrhythmia Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Heart Ventricles/drug effects , Aminobenzoates/chemical synthesis , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Dogs , Drug Design , Electrophysiologic Techniques, Cardiac , Female , In Vitro Techniques , Male , Microelectrodes , Models, Molecular , Molecular Conformation , Structure-Activity Relationship
15.
Drug Discov Today ; 6(14): 745-747, 2001 Jul 01.
Article in English | MEDLINE | ID: mdl-11445466

ABSTRACT

Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.

16.
J Med Chem ; 44(15): 2403-10, 2001 Jul 19.
Article in English | MEDLINE | ID: mdl-11448222

ABSTRACT

QSAR models have been used for designing a series of compounds characterized by a N-phenylpiperazinylalkylamino moiety linked to substituted pyridazinones, which have been synthesized. Measurements of the binding affinities of the new compounds toward the alpha(1a)-, alpha(1b)-, and alpha(1d)-AR cloned subtypes as well as the 5-HT(1A) receptor have been done validating, at least in part, the estimations of the theoretical models. This study provides insight into the structure activity relationships of the alpha(1)-ARs ligands and their alpha(1)-AR/5-HT(1A) selectivity.


Subject(s)
Adrenergic alpha-Antagonists/chemical synthesis , Piperazines/chemical synthesis , Pyridazines/chemical synthesis , Receptors, Adrenergic, alpha-1/metabolism , Adrenergic alpha-Antagonists/chemistry , Adrenergic alpha-Antagonists/metabolism , Animals , Aorta/drug effects , Aorta/physiology , CHO Cells , Cricetinae , HeLa Cells , Humans , In Vitro Techniques , Ligands , Models, Molecular , Muscle Contraction , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Piperazines/chemistry , Piperazines/metabolism , Pyridazines/chemistry , Pyridazines/metabolism , Quantitative Structure-Activity Relationship , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1
17.
Drug Discov Today ; 6(15): 807-809, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11470590

ABSTRACT

Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.

18.
Drug Discov Today ; 6(13): 698-699, 2001 Jul 01.
Article in English | MEDLINE | ID: mdl-11427380

ABSTRACT

Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.

19.
Drug Discov Today ; 6(12): 647-648, 2001 Jun 01.
Article in English | MEDLINE | ID: mdl-11408201

ABSTRACT

Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.

20.
Drug Discov Today ; 6(10): 545-547, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11369294

ABSTRACT

Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.

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