Nonpeptide angiotensin II receptor antagonist

Compound 686 (PNU-97018) is an orally active nonpeptide angiotensin II receptor antagonist without any agonistic activity that has an insurmountably high antihypertensive effect <2002CPB1022, 1995JEP1042, 1995MI880>. 

Kubo K, Inada Y, Kohara Y et al (1993) Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazoles. I Med Chem 36 1772-1784... 

The utility of the sequence has recently been shown by the industrial-scale synthesis of a nonpeptidic angiotensin II receptor antagonist (Scheme 2-46) [121]. 

N. Rankine, J. M. Revill, D. A. Roberts, and S. T. Russell, /. Med. Chem., 35,4027 (1992). New Nonpeptide Angiotensin II Receptor Antagonists. 2. Synthesis, Biological Properties, and Structure-Activity Relationships of 2-Alkyl-4-(biphenylylmethoxy)quinoline Derivatives. P. Biihlmayer, L. Criscione, W. Fuhrer, P. Furet, M. de Gasparo, S. Stutz, and... 

There is enormous activity worldwide seeking to identify nonpeptide agonists or antagonists for both the peptide receptors and the orphans, since it is expected that this will be a fruitful area for drug discovery - witness the success of the nonpeptide angiotensin II receptor antagonists (collectively known as the sartans ) approved several years ago for the treatment of hypertension. 

Losartan is a nonpeptide angiotensin II receptor antagonist used as antihypertensive medication. It can also be considered as a bioprecursor prodrug in so far as, in vivo, the primary alcoholic function is oxidized into a carboxyhc function (Fig. 33.27) and the obtained acid represents the actual active principle. ... 

Figure 8.10 Some bioisosteric replacements for carboxylic acids (top) (Carini, D.J., et al. Nonpeptide angiotensin II receptor antagonists The discovery of a series of A-(Biphenylmethyl) imidazoles as potent, orally active antihypertensives. J. Med. Chem. 1991, 34, 2525-2547), esters (middle) (Kim, K.S., et al. Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2 Synthesis, X-ray crystallographic analysis, and biological activities. /. Med. Chem. 2002, 45, 3905-3927.), and amides (bottom) (Black, W.C., et al. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005,15,4741 744.) The clinical candidate odanacatib (bottom right) incorporates a trifluoroethylamine amide isostere. (Gauthier, J.Y., et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008,18,923-928.)...

Carini, D.J., et al. Nonpeptide angiotensin II receptor antagonists The discovery of a series of iV-(Biphenylmethyl)imidazoles as potent, orally active antihypertensives. J. Med. Chem. 1991, 34, 2525-2547. 

A few new nonpeptide angiotensin II receptor antagonists have been synthesized (93)-(95)... 

Imidazole-5-Acrylic Acids Potent Nonpeptide Angiotensin II Receptor Antagonists Designed Using a Novel Peptide Pharmacophore Model. 

Carini, D.J., Dunda, J.V., Aldrich, P.E., Chiu, A.T, Johnson, A.L., Pierce, M.E., Price, W.A., Santella, J.B., 111, and Wells, G. (1991) Nonpeptide angiotensin II receptor antagonists the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives. Journal of Medicinal Chemistry, 34, 2525-2547. 

Bradbury, R.H., Allott, C.P., Dennis, M., Fisher, E., Major, J.S., Masek, B.B., Oldham, AA., Pearce, R.J., Rankine, N., Revill, J.M., Roberts, D.A., and Russell, S.T (1992) New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and stmcture-activity relationships of 2-aIkyl-4-(biphenylylmethoxy)quinoline derivatives. Journal ofMedicirml Chemistry, 35, 4027-d038. 

Plate 3 Hypothetical superposition of S-8307 with a conformation of A-II predicted by NMR experiments. Reprinted with permission from Duncia, J.V., Chiu, A.T., Carini, D.J. et al. (1990) Discovery of potent nonpeptide angiotensin II receptor antagonists a new class of antihypertensives. Journal of Medicinal Chemistry 33, 1312-1.329. Copyright (1990) American Chemical Society. 

Wienen W, Hauel N, Van Meel JCA, Narr B, Ries U, Entzeroth M (1993) Pharmacological characterization of the novel nonpeptide angiotensin II receptor antagonist BIBR 277. Brit J Pharmacol 110(l) 245-252... 

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