Pyridine bioisosteres

Figure 2.5 Phenyl/pyridine bioisosteric replacement leading to clinical candidate BMS-488043.

Figure 2.14 Pyridine bioisosteric replacement leadingto selective inhibitors of (a4)2( 32)3 nicotinic acetylcholine receptor.

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]. 

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. 

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

Another interesting switch consisted in the progressive passage from desmethyl-minaprine 6 to the bioisosteric thiadiazole 7 (Fig. 1.19), and then to the bioisos-teric thiazoles. Tri-substitution on the phenyl ring and replacement of the aliphatic morpholine by a pyridine led to compound 8 which exhibited some affinity for the receptor of the 41 amino-acid neuropeptide CRF. Further optimization led to nanomolar CRF antagonists such as 9 [41,42]. 

When n = 2, all positions of attachment to the pyridine ring (carbon 2, 3, or 4) result in extremely low potency and activity. When n = 1, attachment to positions 2 and 4 produces practically inert compounds (102). Replacement of the pyridine ring of structure (57) by bioisosteric benzene, 2-thienyl, 2-furanyl, and 2-pyrrolyl ring systems abolishes almost all nicotine-like activity. 

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... 

SAR studies on the heteroaryl moiety in A-84543 (87) revealed that the pyridyl nitrogen in the 3-position is important, and that additional nitrogens in the ring are generally detrimental to activity. It is interesting to note that the 3-methyl-5-isoxazole moiety, which served as a bioisostere for pyridine in ABT-418, is a poor substitute for pyridine in A-84543 (see 99, Fig. 14.9). With respect to the N-methyl analogs, the pyrrolidinylanalog (87) is threefold more active than azetidine (83) and 480-fold more active than piperidine (93). 

A new strategy for the synthesis of DUB-165, a nicotinic acetylcholine receptor (nAChRs), and its bioisosteres series containing pyridine and pyrazine moiety have been described [26]. The key step in the synthesis of bioisoster 37 was the Stille cross-coupling of tributylstannylpyrazine with the vinyl triflate of the A-protccted 9-azabicyclononene 36 [26]. 

FIGURE 15.10 Ligands for central cholinergic receptors with different non-classical bioisosteres of the pyridine ring. 

Two other publications on the bioisosteric replacement of pyridine show similar results. The first paper reports the study of bioisosteric potential of diazines in the field of combined antithrombic thromboxane A2 synthetase inhibitors and receptor antagonists. On the basis of the structure-activity relationships (SAR) observed in this study, it turned out that only the 2-pyrazinyl, 4-pyridazinyl... 

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. 

FIGURE 15.12 Bioisosteric replacements of the pyridine ring in a series of factor Xa inhibitors. 

Abe et al. reported that the imidazol [l,2-a]pyridine moiety of the basic framework of a class of the non-peptide bradykinin B2 receptor antagonists (11, Figure 15.14) could be successfully replaced by several heterocyclic bioisosteres. Among those, the l-methyl-2-methoxy-l//-benzimidazole, 2-methylquinoxaline and 2-methylquinoline derivatives showed potent B2 binding affinities against both human and guinea pig B2 receptors (Figure 15.14). 

Most of them showed different activities on the central nervous system. A series of these compounds (Figure 15.15) are acetylcholinesterase inhibitors with variable bioisosteres of the central pyridazine. The replacement by pyridine, 1,2,4-thiadiazole and triazines yields compounds with weaker but stiU acceptable activity. 

Examples from literature show that there are several non-classical bioisosteres for the pyridine system or the pyridazine system. Which is the rationale behind this in order to choose the most appropriate analog to start with An indication could be given by the comparison of the boiling points... 

Selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) give a nice example of bioisosters of heterocycles. The comparison of the most potent selective COX-2 inhibitors (Figure 15.17) suggests that isoxazoles, pyridines, and pyrazoles are good bioisosteres of each other as well as nitrophenol, and indanones. ... 

Whereas both enantiomers of pinacidil possess cardiovascular properties, bioisosteric replacement of the cyanoguanidine group by a nitroethenyl group and of the pyridine moiety by an ethoxyphenyl group has produced a disparity in the properties of the enantiomers [32]. Electrophysiological examination of the... 

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