Bioisosteric substituent

Figure 7.3 A web tool for identification of bioisosteric substituents based on similarity in their properties used at Novartis.

In Part Two, a number of data mining methods were reported that extract relevant bioisosteric pairings from the hterature. The extraction of this information requires graph matching algorithms and fragmentation methods to identify potential bioisosteric substituents. 

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... 

To correctly address the problem of identification of target-specific privileged motifs, one should take into account the phenomenon of bioisosterism [26]. Thus, several different bioisosteric structures can constitute only one distinct privileged structural motif. In order to include all possible bioisosteric analogs into one cluster, we use a special algorithm of ChemoSoft based on a collection of rules for bioisosteric conversions described in literature. AH bioisosteric analogs are considered similar with similarity coefficient 1 if they have identical substituents around the central bioisosterically transformed fragment. 

Ertl, P. Cheminformatics analysis of organic substituents identification of the most common substituents, calculation of substituent properties, and automatic identification of dmg-like bioisosteric groups. J. Chem. Inf. 

The frequently observed bioisosteric relation of benzene and thiophene applies to the clonidine series as well. Reaction of the thiophenyl thiourea (85-1), in which the amine group is flanked by substituents as in the prototype, with methyl iodide and a base gives the corresponding methyl thioether (85-2). Treatment of that intermediate with ethylene diamine leads to the formation of an imidazoline ring and the antihypertensive agent, tiamenidine (85-3) [90], shown as its imino tautomer. 

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... 

Steric effects. As the second smallest substituent, fluorine closely resembles hydrogen s steric requirement for binding to an active site. This makes replacement of hydrogen by fluorine a common bioisosteric replacement [11],... 

No two substituents are exactly alike. Any substitution impacts size, shape, electronic distribution, lipophilicity, pKa, chemical reactivity, susceptibility to metabolism, and the like. The bioisosteric approach is the total change induced by substituent replacement on the potency, selectivity, duration of action, bioavailability and toxicity, of an agrochemical. The following groups are examples of... 

On the basis of this equation Zou et al. have concluded that hydrophobic compounds with inductively electron-donating ortho substituents would be favorable for the activity [193]. In continuation of this, Zou and coworkers have carried out CoMFA-based 3D-QSAR analysis of these compounds together with 5-[l-aryl-l,4-dihydro-6-methylpyridazin-4-one-3-ylj-2-arylamino- 1,3,4-oxadiazoles [ 194]. Here also the antifungal activity of these compounds has been found to be well explained by their steric and electrostatic properties. In addition to this, it has confirmed the bioisosterism... 

In a systematic search for novel analogues of the anti-inflammatory indole-3-acetic acid derivative indomethacin (216), scientists at the Pierrel Laboratories in Milan reasoned that substitution of an azido group for the 4-chloro substituent on the A-benzoyl ring might represent an effective bioisosteric replacement, and thus confer interesting biological properties to the molecule [266]. l-(4-Azidobenzoyl)-5-methoxy-2-methyl-l/f-indole-3-acetic acid (zidometacin) (217) was synthesized and evaluated for its... 

In continuation of efforts to identify Mi-selective muscarinic agonists capable of crossing the blood-brain barrier, the 3-carbo-methoxy group of arecoline was replaced by bioisosteric 1,2,5-oxadiazole (154) or by 1,2,5-thiadiazole rings with oxygen ether substituents at position 3 (155)or with thioether substituents at position 3 (156) (190). 

Isoxazole and Isothiazole Derivatives. Bioisosteric replacement of the pyridine ring in nicotine generated a series of novel isoxazole compounds that are selective and potent neuronal nAChR agonists, as exemplified by ABT-418 (71) (Table 14.8) (299). Among the variety of substituents examined at C3 cf the isoxazole, methyl turns out to be optimal, even though other substituents, such as C2-C4 linear alkyl, CF Br, and benzyl (not phenyl), still provide potent analogs. The 3-des-methyl... 

This table shows some physicochemical parameters for six different substituents. If the most important physicochemical parameter for biological activity is other hand, the dominant parameter is it, then a more suitable bioisostere for SOCH3 (-1.58) would be S02CH3 (-1.63). 

Some non-classical isosteres are reported in Table 15.5 and from a brief glance it can be noticed that they do not obey the steric and electronic definition of classical isosteres. A second notable characteristic of non-classical bioisosteres is that they do not have the same number of atoms as the substituent or moiety for which they are used as a replacement. 

FIGURE 15.61 An example of bioisosterism, or non-classical isoster-ism, the methylsulfonamide substituent has comparable acidity to the phenolic hydroxyl group. ... 

In the losartan molecule, the substituted imidazole moiety is attached to the typical tetrazolyl-diphenyl unit (Figure 19.15). In practicing analog synthesis, the Novartis scientists conserved unchanged this latter part of the molecule but tried to prepare a bioisosteric equivalent of the substituted imidazole possessing similar interaction possibilities. The lipophilic n-butyl chain was maintained, the CN dipole was replaced by a CO dipole, and the ensemble chlorine substituent plus two imidazolic carbon atoms was replaced... 

Another example for the bioisosteric equivalence of aromatic bulky polar substituents (in this case chlorine) and ortho difluorination is a second generation analog of the anti-HIV drug Efavirenz. The difluoro analog acts as a reverse transcriptase inhibitor with a different pattern of resistance [62] (Scheme 4.29). 

Brotilzolam represents a twofold modification the fused benzo ring is replaced by the bioisosteric thiazole (the Br substituent apparently in the No. 7 equivalent position), and a triazolo fusion also is carried out. The drug, which is marketed in Germany and Portugal, is about equipotent to triazolam. 

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