Drug bioisosterism

Patani G A and E J LaVoie 1996. Bioisosterism A Rational Approach in Drug Design. Chemical Reviei 96 3147-3176. 

Various bioisosteric replacements for a phenolic hydroxyl have been explored. One such, a lactam NH, is incorporated into the design of the 3-adrenergic blocker, carteolol O)- The fundamental synthon is carbostyril derivative K This is reacted in the usual manner with epichlorohydrin to give which is in turn reacted with t-butylamine to complete the synthesis of carteolol (3 ), a drug that appears to have relatively reduced nonspecific myocardial depressant action. Carrying this de-... 

Andersen, K. E., Sprensen, J. L Huusfeldt, P. 0., Knutsen, L. J., Lau, J., Lundt, B. F., et al. (1999) Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates../. Med. Chem. 42,4281 4291. 

Furan-containing molecules are found in both natural products and pharmaceuticals. At one time, furfural was produced in great quantities from corncobs. Perillene, a secondary plant metabolite, is an example of naturally occurring furans. Furan is frequently used as a bioisostere of a benzene ring in medicinal chemistry. For example, Ranitidine (Zantac) marketed by Glaxo was one of the first blockbuster drugs with annual sales over 1 billion dollars. 

Meier E, Frederiksen K, Nielsen M, Pharmacological in vitro characterization of the arecoline bioisostere Lu 25-109-T, a muscarinic compound with M-l-agonistic and M-2/M-3 antagonistic properties. Drug Dev Res 40 1—16, 1997. 

Burger, A. (1991) Isosterism and bioisosterism in drug design. Prog. Drug Res. 2>1, 287-371. 

Hallucinogen-like activity of these compounds as potential bioisosteres of T,T-dimethyltryptamine was evaluated in the two-lever drug discrimination paradigm using LSD- and DOI-trained rats (LSD = lysergic acid diethylamide DOI = 2,5-dimethoxy-4-iodoamphetamine). 

Figure 1.5 Bioisosteres. These are biologically equivalent molecular fragments that can be used to replace portions of a drug molecule.

Figure 3.1 Peptidomimetic chemistry attempts to produce a non-peptidic drug to mimic a bioactive peptide. In Step A, the smallest bioactive fragment of the larger peptide is identified in Step B, a process such as an alanine scan is used to identify which of the amino acids are important for bioactivity in Step C, individual amino acids have their configuration changed from the naturally occurring L-configuration to the unnatural D-configuration (in an attempt to make the peptide less naturally peptidic ) in Step D, individual amino acids are replaced with atypical unnatural amino acids and amino acid mimics in Step E the peptide is cychzed to constrain it con-formationally finally, in Step F, fragments of the cyclic peptide are replaced with bioisosteres in an attempt to make a non-peptidic organic molecule.

Despite many clinical similarities, these agents differ in their absorption, dosing with other drugs, and duration of actions for example, quinapril has a of 3 hours whereas ramipril has a of 13-17 hours. The quest for ACE inhibitors devoid of the sulfhydryl group also led to the evaluation of phosphonate-containing inhibitors, on the basis of the notion that phosphinic acid is bioisosterically equivalent to sulfhydryl and carboxylate groups in terms of Zn " chelation. This lead to the development of fosinopril... 

Bioisosterism a useful strategy for molecular modification and drug design. Curr. Med. Chem., 12, 23-49. 

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