Bioisosterism biological isosterism

Baclofen, 121 Bamethan, 39 BAS, 96 BCNU, 12 Becanthone, 413 Beckett-Casey rule, 328 Beloxamide, 56 Benapryzine, 74 Bendazac, 351 Benfurodil, 355, 356 Benorterone, 156 Benoxaprofen, 356 Benperidol, 290 Benproperine, 100 Benzbromarone, 354 Benzetimide, 293 Benzilate esters, 74 Benzilonium bromide, 72 Benzindopyrine, 343 Benzoctamine, 220 Benzodepa, 122 Benzothiadiazines, 383 Benztriamide, 290 Benzydamine, 350 Betahistine, 279 Bioisosterism (see also biological isosterism), 278... 

Table 4.3 Examples of isosteres. Each horizontal row represents a group of structures that are isosteric. Classical isosteres were originally defined by Erlenmeyer as atoms, ions and molecules with identical shells of electrons. Bioisosteres are groups with similar structures that usually exhibit similar biological activities...

Recognizing the usefulness of the isosterism concept in the design of biologically active molecnles, Friedman proposed to call bioisosteres componnds... 

Biologically active molecules containing amide bonds suffer usually of pharmacokinetic liability. In order to increase their stability, bioisosteric transformation of the carboxamide have been performed and yielded a lot of successful examples especially in the area of petidomimetic. The isosteric replacements for peptidic bonds have been summarized by Spatola and by Fauchere. " The most used and well-established modihcations are iV-methylation, configuration change (o-conhguration at Ca), formation of a retroamide or an a-azapeptide, use of aminoisobutyric or dehydroamino acids, replacement of the amidic bond by an ester [depsipeptide], ketomethylene, hydroxyethyl-ene or thioamide functional group, carba replacement of the amidic carbonyl, and use of an olefinic double bond (Figure 15.33). 

The use of the word isosterism has largely been taken beyond its original meaning when employed in medicinal chemistry, and Thomber proposes a loose and flexible definition of the term bioisostere Bioisosteres are groups or molecules which have chemical and physical similarities producing broadly similar biological effects . 

When a lead compound is first discovered for a particular disease state, it often lacks the required potency and pharmacokinetic properties suitable for making it a viable clinical candidate. These may include undesirable side effects, physicochemical properties, other factors that affect oral bioavailability (see Chapter 9), and adverse metabolic or excretion properties. These undesirable properties could be the result of specific functional groups in the molecule. The medicinal chemist therefore must modify the compound to reduce or eliminate these undesirable features without losing the desired biological activity. Replacement or modification of functional groups with other groups having similar properties is known as isosteric replacement, or bioisosteric replacement. ... 

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.)...

---