Carboxylic acid bioisosteres in drug design europe pmc. Bioisosteres in drug design posted on march 21, 2011 by mcb an excellent j. The replacement of a carboxylic acid with a surrogate structure, or bioisostere, is a classical strategy in medicinal chemistry. Drug design with the help of computers may be used at any of the following stages of drug discovery isosterism played good role in designing of desired drugs.
For omega3carboxylic acids, the following should be considered. In drug design1 the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure. The identification of bioisosteres as drug development. The carboxylic acid functional group adds to the hydrophilicity of the drug as well as to its polarity and this may impede the bioavailability. N n n r n n n n r n n n n hn r phthn co2me cn nan3, nh4cl dmf, 90 oc phthn co2me n h n n n hn n n n h o co2h n n nh o tomudex analogues j. The present disclosure provides compounds that include a tetrazolone derivative of a carboxyl group of an active agent. Piperazinebased analogues may advantageously alter important pharmacokinetic properties when grafted onto molecular scaffolds. Bioisosteres in medicinal chemistry drug discovery. Tetrazolones as a carboxylic acid bioisosteres patent. The use of bioisosterism in drug design and molecular. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical. Boron substituents provide versatile reactivity, and their utility has been emerging in pharmaceutical contexts.
Omega3carboxylic acids is available only with your doctors prescription. Welcome to the swissbioisostere database this website provides access to our knowledgebase of molecular replacements, useful for compound optimization in drug design. Several carboxylic acid surrogates have been reported that display utility in drug design figure 1. Review article squaryl molecular metaphors application to. In addition, we designed and synthesized a series of 5arylheteroarylisoxazole3carboxylic acids as biological isosteric analogues of. Omega3carboxylic acids advanced patient information. Photoinduced decarboxylative borylation of carboxylic.
Lavoie department of pharmaceutical chemistry, college of pharmacy, rutgers, the state university of new jersey, piscataway, new jersey 088550789. Opportunities and challenges for fatty acid mimetics in drug discovery. Carboxylic acids and their bioisosteres request pdf. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context i. Isosterism and bioisosterism in drug design pdf may 7, application of isosteres in drug design oxetanes in drug discovery 2 exchangeable group isosterism in which the properties of. Routes to drug design via bioisosterism of carboxyl and sulfonamide. Christos mitsos isosteresin medicinal chemistry group meeting 212006 r n hn3 base. Herein, we summarize the key properties and provide representative examples describing the use of each of the carboxylic acid bioisosteres in drug design. Carboxylic acid bioisosteres in drug design ballatore. Review article squaryl molecular metaphors application. The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes. Omega3 carboxylic acids are fishoil derived mixture of free fatty acids, that are used together with low fat and low cholesterol diet to lower high triglyceride fat levels. Optimization of lead identification isostersim the active part.
Carboxylic acid bioisosteres in drug design request pdf. May 17, 2019 isosterism and bioisosterism in drug design. The first part provides an overview of bioisosterism, classical bioisosteres and typical molecular. By tim cheeseright at cresset biomolecular discovery the identification of bioisosteres as drug development candidates figure 1. In drug design, the most important examples showcasing the utility of tetrazoles as carboxylic acid isosteres include several nonpeptidic angiotensin ii type 1 at1 receptor antagonists. Bioisosteres in medicinal chemistry methods and principles in medicinal chemistry. With the swissbioisostere database, we provide access to a large knowledgebase of molecular replacements and information on their observed impact on biological activity, to aid medicinal chemists in their quest to identify clinical candidates and to facilitate drug design research via an interface that requires no specific training. Meanwell department of medicinal chemistry, bristolmyers squibb pharmaceutical research and development, 5 research parkway, wallingford, connecticut 06492, united states 1. Synopsis of some recent tactical application of bioisosteres in drug design nicholas a. Matched molecular pair analysis was used to evaluate the ability of a tetrazolone group to act as a bioisostere of a carboxylic acid. As such, it provides a ready reference on the principles and methods of bioisosteric replacement as a key tool in preclinical drug development. Abstract the carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well.
Introduction the concept of isosterism between relatively simple chemical. Isosteresin medicinal chemistry group meeting christos. The use of bioisosterism in drug design and molecular modification priyanka l. Carboxylic acid bioisosteres in drug design ncbi nih.
The importance of the carboxylic acid functional group in drug design is illustrated by the fact that 450 marketed drugs are carboxylic acid containing molecules. First paper to highlight the importance of the average electon density descriptor in anionic bioisosteres in drug design. The main use of this term and its techniques are related to pharmaceutical sciences. The carboxylic acid functional group plays a cardinal role in the biochemistry of living systems as well as in drug design. The at1 receptor is a member of the g proteincoupled receptor gpcr superfamily that plays an important role in vasoconstriction. Substrates and inhibitors of gammaaminobutyric acid aminotransferase containing bioisosteres of the carboxylic acid group. The optimal bioisosteres of the phenolic function should have approximately the same size as the hydroxyl itself and should have approximately the same acidity range weak acid and be able to form hydrogen bonds.
In this particular context, the most important physicochemical parameters are arguably the. Naka and coworkers reported some bioisosteres of a tetrazole ring and their applications in angiotensin ii receptor antagonists. Nov 09, 2017 routes to drug design via bioisosterism of carboxyl and sulfonamide groups. Coppermediated synthesis of druglike bicyclopentanes. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result.
Request pdf carboxylic acid bioisosteres in drug design the carboxylic acid functional group can be an important constituent of a pharmacophore. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this. A wide variety of endogenous substances, such as amino acids, triglycerides and prostanoids, possess the carboxylic acid moiety. In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure. Request pdf carboxylic acid bioisosteres in drug design the carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also. Jan 29, 20 several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context i. The unique properties of fluorine have led to its widespread application in drug design as an isostere for hydrogen, since incorporation of fluorine can productively modulate a range of properties of interest to medicinal chemists.
Routes to drug design via bioisosterism of carboxyl and sulfonamide groups. Routes to drug design via bioisosterism of carboxyl and. The carboxylic acid functional group is part of the pharmacophore of many commercial drugs ranging from nonsteroidal antiinflammatory medicines nsaids. Synopsis of some recent tactical application of bioisosteres in drug design doi. The drug should have a good selectivity for its target 2. Morpholine bioisosteres for drug design more than 20 fdaapproved drugs contain the morpholine moiety, although it is often metabolically labile. In drug design 1 the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure. In medicinal chemistry, bioisosteres are chemical substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to another chemical compound. The drug should have a good level of activity for its target 3. Drug designoften referred to as rational drug design or simply rational designis the inventive process of finding new medications based on the knowledge of a biological target. Jul 28, 2019 drug design with the help of computers may be used at any of the following stages of drug discovery isosterism played good role in designing of desired drugs.
Application of this technology to the search for bioisosteres results in relevant, nonobvious suggestions that make a significant impact on the drug development process. Morpholinebased analogues may advantageously alter important pharmacokinetic properties such as lipophilicity and metabolic stability when grafted onto molecular scaffolds. In this case, the replacement of the phenol by heterocyclic nhcontaining rings was performed in order to slow metabolism and hence to improve oral bioavailability. Squarate and tetrazole, which are other common bioisosteres of carboxyl, have ic 50 nm of 25 and 3, respectively. The author gives a brief introduction to the concept of biosisosterism classical and nonclassical but concentrates on pulling together numerous. The ic 50 nm drops from 275 with the carboxylic acid to 100 with the sulfonamide group. Swissbioisostere a database of molecular replacements. Once the acids are activated with phthalimide substituents, they can react with catecholborane dimers. One such application has been its use in the aryl acetic acids which. Isosteresin medicinal chemistry group meeting christos mitsos. This will encourage research and help in the pursuit of a worthwhile objective, be it the enrichment of knowledge or the elaboration of a practical purpose. Isosterism and bioisosterism in drug design springerlink. Whilst this is very comprehensive it contains a lot of transformations that were never intended to be bioisosteric replacements.
Compound 7, a tetrazolone of the antihypertensive drug, telmisartan 6, was shown to be a potent at1 antagonist kb 0. A carboxyl group could be substituted by a sulfonamide bioisostere 37 in angiotensin ii receptor antagonists 38. To overcome this problem, replacement of carboxylic acid with bioisostere which has similar physicochemical properties. This disclosure also relates to pharmaceutical compositions that include these compounds, methods of using these compounds in the. The replacement of a carboxylic acid with a surrogate structure. Piperazine bioisosteres for drug design more than 100 fdaapproved drugs contain the piperazine moiety. Carlo ballatore, donna m huryn, amos b smith pmid 23361977. A frequently used bioisosteric modification in drug design is to replace a carboxylic acid group with 1htetrazole, as can be seen above both have similar pka 4.
A frequently used bioisosteric modification in drug design is to replace a carboxylic acid group with 1htetrazole. Swissbioisostere a database of molecular replacements for. Bioisosteric replacements cambridge medchem consulting. Although unedited, the content has been subjected to preliminary formatting. Coppermediated synthesis of druglike bicyclopentanes xiaheng zhang, russell t.
Bioisosteric replacements bioisosteres a bioisostere is a molecule resulting from the exchange of an atom or of a group of atoms with an alternative, broadly similar, atom or group of atoms. This success led to the application of this bioisosteric replacement to other categories of drugs. Structure property relationships of carboxylic acid isosteres. Optimizing drug properties leadtodrug design uzh chemistry. Written with the practicing medicinal chemist in mind, this is the first modern handbook to systematically address the topic of bioisosterism. In every scientific undertaking that is to break new ground, one has to have a goal, a working hypothesis, or a leading idea or fact. Bioisosteric replacement as a tool in antihiv drug design mdpi. Drugs must have both hydrophilic and lipophilic characteristics. Paola ciapetti, bruno giethlen, in the practice of medicinal chemistry fourth edition, 2008. The organic chemistry of drug design and drug action, third edition, represents a unique approach to medicinal chemistry based on physical organic chemical principles and reaction mechanisms that.
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