Acidic isostere

It took nearly a decade from the time the first purified IN protein was reported to the elucidation of the basic pharmacophore through the discovery of diketo acids (DKAs) and acid isostere analogs which were nearly simultaneously reported by independent groups [7]. Examples of these early generation IN inhibitors (INIs) are shown in Figure 1. 

Figure 1 Diketo acid (DKA) and acid isostere analogs.

K.W. Laue, C. Muck-Lichtenfeld, G. Haufe, Enantioselective syntheses of 2-amino-4-fluoropent-4-enoic acids. Isosteres of asparagine, Tetrahedron 55 (1999) 10413-10424. 

A review on 5-substituted-l//-tetrazoles as carboxylic acid isosteres in medicinal chemistry has been published <02BMC3379>. The mechanisms of tetrazole formation by addition of azides to nitriles have been investigated by density functional theory calculations <02JA12210>. 

An optimised solid-phase method for the generation of diverse a-amino-alkyl or -aryl phosphonates derived from peptides and polymer-assisted solution-phase parallel synthesis of dipeptide p-nitroanilides and dipeptide diphenyl phosphonates have been reported. A modular method for the construction of polypeptides containing the Phe-Arg phosphinic acid isostere has been described. A novel methodology for the solid-phase synthesis of phosphinic peptides has been developed in which the phosphorus-carbon bond was formed... 

A modular method for the construction of polypeptides (334) containing the Phe-Arg phosphinic acid isostere has been reported (Figure 52). " ... 

Calleri, E., Massolini, G., Loiodice, F., Fracchiolla, G.,Temporini, C., Felix, G., Tortorella, P., Caccialanza, G. Evaluation of a penicillin G acylase-based chiral stationary phase towards a series of 2-aryloxyalkanoic acids, isosteric analogs and 2-arylpropionic acids,/. Chromatogr. A, 2002,958, 131-140. 

TABLE 15.11 Carboxylic Acid Isosteres Direct Derivatives A... 

TABLE 15.13 Carboxylic Acid Isosteres Non Planar Sulfur-or Phosporus-Derived Acidic Functions ... 

K., Lancaster, M. E., Lee, F, Hart, R., Paulik, M. A., Sherman, B. W, True, T., Cowan, C. Synthesis and evaluation of potent and selective beta(3) adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres. J. Med. Chem. 2002,45(3), 567-583. 

Paulvannan, K., and Stille, J.R., Conformationally restricted P-amino acid isosteres prepared through regioselectivity controlled aza-annulation. Tetrahedron Lett., 34, 8197, 1993. 

Lohse, P.A., and Eelber, R., Incorporation of a phosphonic acid isostere of aspartic acid into peptides using Emoc-solid phase synthesis, Tetrahedron Lett., 39, 2067, 1998. 

The cellular and in vivo use of natural phosphoamino acid-containing peptides has severe limitations because, in addition to the poor chemical stability of the 0-phosphate group, they are subjected to dephosphorylation by phosphatases and are poorly absorbed into cells. These circumstances and the potential therapeutic use of compounds containing enzymatically and chemically stable phosphoamino acid isosteres have motivated the synthesis of phosphoamino mimetics. Figure 20 shows some selected examples of phosphotyrosine (44 [175-177], 45 [176], 46 [178], 47 [179], 48-49 [177], 50 [180], 51 [177], 52 [181], 53 [182], 54 [183], 55-56 [184,185], 57 [186]), phosphoserine (58 [187], 59 [188], 60 [189,190], and phosphothreonine (61 [191]) mimetics. These building blocks have been incorporated into peptides and peptidomimetics by solid-phase synthesis using standard procedures [175,179,182,183,189,192-198]. 

In a more recent example of the application of isosterism, we have pioneered the use of the cyclopropyl acylsulfonamide moiety as a carboxylic acid isostere in the context of inhibitors of HCV NS3 protease [7, 8]. This moiety confers a significant increase in potency, 50-fold in the matched pair of inhibitors 6 and 7, and has been widely adopted by the industry as a design element [9]. 

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