Bioisosteres/bioisosterism

The use of the word isosterism has largely been taken beyond its original meaning when employed in medicinal chemistry, and Thomber proposes a loose and flexible definition of the term bioisostere Bioisosteres are groups or molecules which have chemical and physical similarities producing broadly similar biological effects . 

Patani G A and E J LaVoie 1996. Bioisosterism A Rational Approach in Drug Design. Chemical Reviei 96 3147-3176. 

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). ... 

Bioisosteric relations constitute one of the more familiar tools in medicinal chemistry. There are thus sets of atoms that can often be interchanged without much... 

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-... 

The clinical acceptance of the dihydrochlorothiazide diuretics led to the synthesis of a quinazolinone bioisostere, fenquizone (54). The synthesis follows the usual pattern of heating... 

Cefotiam (67) has an acyl aromatic C-7 side chain bioisosteric with an anilino ring. It can be prepared by... 

As a direct appUcation a potent C2-symmetric HIV-1 protease inhibitor (with two tetrazoles as carboxyl group bioisosteres) was prepared in one pot [77]. The process involved microwave-promoted cyanation followed by conversion of the nitrile group in a tetrazole with azide (Scheme 64). It is notable that the fimctionahzation was achieved so smoothly without side reactions such as the ehmination of water. 

Phosphonate analogs to phosphate esters, in which the P—0 bond is formally replaced by a P—C bond, have attracted attention due to their stability toward the hydrolytic action of phosphatases, which renders them potential inhibitors or regulators of metabolic processes. Two alternative pathways, in fact, may achieve introduction of the phosphonate moiety by enzyme catalysis. The first employs the bioisosteric methylene phosphonate analog (39), which yields products related to sugar 1-phosphates such as (71)/(72) (Figure 10.28) [102,107]. This strategy is rather effective because of the inherent stability of (39) as a replacement for (25), but depends on the individual tolerance of the aldolase for structural modification close... 

Figure 10.28 Complementary routes for the stereoselective synthesis of hydrolytically stable sugar phosphonates, either from the bioisosteric phosphonate analog of DHAP or from phosphonylated aldehydes.

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... 

Table 6.40 THIAZOLE- AND TRIAZOLE-BASED BIOISOSTERES OF RIMONABANT (382) -/JV VITRO DATA [311]...

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 applicability of such VS in combination with tools available include situations where portions of any molecule need replacement with bioisosteric fragments. In this regard, BROOD software [105] and MOE [222] provide automated tools for fragment removal, replacement, and minimization to relieve any strain in the molecular assembly step and provide a database of fragments(isosteres) that could be enhanced in custom fashion by an enterprise as well. These software allow facile FBVS in 3D. Since this software has become available within the last 2 years, there seem to be a dearth of use cases in the published literature. However, anecdotal reports indicate that these are being used regularly in industry and the Websites of these two vendors provide adequate information for the inquisitive reader. 

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. 

Substitution of a pyridine ring for a benzene ring often is compatible with retention of biological activity and occasionally this moiety is an essential part of the pharmacophore. Such substitution of =N for CH= is an example of the common medicinal chemical strategy known as bioisosterism. 

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