Bioisosteric replacement analogs

The structure of a catechol itself can be replaced by analogous heterocycles in various derivatives. All these compounds share the ability to chelate metal atoms and to form hydrogen-bonded second rings, the benzimidazole imitates this by way of a covalent ring structure.182 A successful bioisosteric replacement of a phenol or a catechol moiety is the 2-aminothiazolyl moiety. Active dopaminergic compounds which possess such a moiety are B-HT 920 (32)183 and pramipexole (19).146,154,155... 

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... 

A-(6-Chloronaphthalen-2-)sulfonylpiperazine derivatives 4 and 5 (Figure 15.12) are potent factor Xa inhibitors. Haginoya et al proposed to replace the pyridine-phenyl or the pyridine-piperidine residue by a fused-bicyclic ring which contains an aliphatic amine and a pyridine to yield the compound 6 that has an interesting factor Xa inhibitor activity. The bioisosteric replacement of the pyridine moiety of the 6-methyl-5,6,7,8-tetrahydro-[l,6]naphthyridine by phenyl, thiophene, or thiazole analogs yielded analogs with similar or better antifactor Xa activity, but also to conserve a moderate bioavailability. 

Bioisosteric replacement of the hydroxyl anilide moiety of hydroxyflutamide (8) with a hydantoin analog by Raynard et al. in 1977 resulted in nilutamide (9) or Nilandron [48, 54], which was commercialized in 1987 by Aventis Pharma for... 

The rationale applied in miniaturizing renin inhibitors to achieve clinically useful compounds by eliminating their protein nature and increasing inhibitory potency has, of course, wider ramifications. Judicious use of bioisosteric replacements and the relevancy of the transition-state analogy concept can also be applied with similar success to polypeptide neurotransmitters. 

Figure 9.2 Structural analogs of classical bioisosteric replacement of antipsychotic drugs.

Figure 9.3 Structural analogs of nonclassical bioisosteric replacement.

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... 

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

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... 

An illustration of the second strategy is provided by the para-cyano analogs of the non-nutritive sweetener suosan (Figure 41.18). The replacement of the planar carboxylic group by the bioisosteric tetrazolyl group yields less potent, but still sweet compounds. ... 

Figure 4.21 Phosphates, which are sensitive to hydrolysis and enzymatic degradation, can be replaced by the corresponding bioisosteric methylphosphonates and their mono- and difluori-nated analogs [65], The acidity of the phosphate group (second pK ) is best matched by iso-acidic a-fluoromethylphosphonates, the polarity by isopolar a,a-difluoromethylphosphonates.

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