Bioisostere replacement

A rather distantly related analogue incorporating a 3-di-carbonyl moiety as a bioisosteric replacement for a carboxyl, aril done (55), blocks the uncoating of polio virus and herpes simplex virus type I and thus inhibits infection of cells and l.he early stages of virus replication. Thus effective therapy would require careful timing as it does with amantidine. 

Because of resonance stabilization of the anion, a tet-nazolyl moiety is often employed successfully as a bioisosteric replacement for a carboxy group. An example in this subclass is provided by azosemide (27). Benzonitrile analogue is prepared by phosphorus oxychloride dehydration of the corresponding benzamide. Next, a nucleophilic aromatic displacement reaction of the fluorine atom leads to The synthesis concludes with the 1,3-dipolar addition of azide to the nitrile liinction to produce the diuretic azosemi de (27). ... 

Various bioisosteric replacements for a phenolic hydroxyl have been explored. One such, a lactam NH, is incorporated into the design of the 3-adrenergic blocker, carteolol O)- The fundamental synthon is carbostyril derivative K This is reacted in the usual manner with epichlorohydrin to give which is in turn reacted with t-butylamine to complete the synthesis of carteolol (3 ), a drug that appears to have relatively reduced nonspecific myocardial depressant action. Carrying this de-... 

Table 2.3 BIOISOSTERIC REPLACEMENTS OF THE C-TERMINAL CARBOXYLIC ACID...

Patent applications from Pfizer disclosed 1,5-diaryl-pyrazoles bearing bioisosteric replacements for the 3-carboxamide moiety. One application showed that the amide could be replaced by a-aminoketones as exemplified by compound (416) [284]. The corresponding alcohols and their ethers were also described, including compounds that allowed the amine substituent and ether to form a ring system, such as a morpholine unit. This application also allowed for the replacement of the 1,5-diaryl-pyrazole by a 1,2-diaryl-imidazole bearing a 3-carbonyl substituent, as exemplified by compound (417). A further patent application from Pfizer claims compounds in which imidazoles replace the 3-carboxamide moiety in the 1,5-diaryl-pyrazole... 

Merck has recently utilised a furo[2,3-b]pyridine core (554) as a bioisosteric replacement for the pyrazole scaffold of rimonabant (382) [328]. The same basic pharmacophore, that of two halo-substituted aryl groups and a third hydrophobic motif proximal to a hydrogen-bond acceptor, can be witnessed in the benzodioxole-based compounds, such as (555), disclosed by Roche [329]. 

The ionizability of compounds affects other parameters such as solubility, permeability, and ultimately oral bioavailability, so it may be important to track changes in the pka of new compounds. Calculated pka values can be used when planning the synthesis of new compounds, but it is also a good idea to confirm these values experimentally. An example where this strategy can be useful is in the search for bioisosteric replacements for a carboxylic acid group. 

Anthranilide bioisosteric replacement has also been pursued as a strategy for identifying novel GPR109A agonists. For example, five-membered heterocycles (F) in particular thiophene or furan regioisomers as bioisos-teres of benzene have been disclosed in patent applications by a number of groups (e.g., 23 and 24) [69-72]. 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

The use of fluorine to modulate properties including potency, selectivity, pharmacokinetics, and toxicity has have been highlighted. Fluorine has also been suggested as a potential bioisosteric replacement for a number of functional groups, examples of which are presented in the final section. 

Extension of the ring numbers, bioisosteric replacement of the benzene ring, and conversion of the quinolone system to the corresponding quinalizinone system has been a subject of research interest during the past decade. For example, Jordis et al. [38] recently reported the syntheses of a series of linear benzo- or pyrido-ciprofloxacin (lin-benzo- and lin-pyrido-ciprofloxacin)... 

In conclusion, a variety of mutually different pTyr mimetics incorporated in peptide-type derivatives have been investigated. However, an overall satisfactory bioisosteric replacement has not yet been identified. 

These databases are a rich source of information, yet they do not capture an element of interest, namely the biological endpoint there is no searchable field to identify, in a quantitative manner, what is the target-related activity of a particular compound. Such information is important if one considers that (a) not all chemotypes indexed in patent databases are indeed active - some are just patent claims with no factual basis and that (b) not aU chemotypes disclosed as active are equally active, or selective for that matter, on the target of choice. Furthermore, should one decide to pursue a certain interaction hotspot in a given ligand-receptor structure (assuming good structure-activity models are available), it would be very convenient to mine structure-activity databases for similar chemotypes to use as potential bioisosteric replacements. 

Oxadiazoles owe their importance mainly to their biological activities. A basic idea behind many developments is that the 1,2,4-oxadiazole ring is a hydrolysis resisting bioisosteric replacement for an ester functionality <90JMC1128,91JMC140,91QSAR109>. 

The majority of NMDA agonists are closely related to the structure of glutamic acid. Thus, 4-methylene-L-glutamic acid (4.211) is a potent NMDA agonist. Bioisosteric replacement of a carboxylate group also produces agonists D,L-(tetrazol-5-yl)glycine (4.212), in which a tetrazole bioisostere replaces a carboxylate, is a potent NMDA... 

Note broadly similar biological properties. Bioisosteric replacement must allow a number of properties to remain, and some to be altered. Thus, one may allow selective binding to a receptor to remain, but alter an agonist to an antagonist. This is the classical approach to many drugs that was pursued long before the term bioisostere was invented. 

Bioisosteric replacement can be made from a position of knowledge, if the desirable properties of the substituent or substructure to be changed have been characterized. Such properties can include (with typical parameters) (a) size (volume, molar refractivity, surface area, Taft s) (b) shape (Verloop length and breadth, bond angles, interatom distances) (c) lipophilicity (log P, tt,/) (d) solubility (log S) (e) ionization state (pKg, a) ... 

Bioisosteric replacement of a substituent or group can be made without a priori knowledge of desirable properties, provided that at least two (but preferably more) groups giving the required response can be identified, and... 

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