Bioisosteria
Bioisosteria is a term used in medicinal chemistry . Two molecules are called bioisosts if they show a biologically comparable effect in vivo (i.e. in the living system) and are isostere . An example would be the opiates , most of which are mutually bioisosteric because they have almost the same biological effect. The term is used in particular in connection with the so-called rational drug design . The literal translation of bioisosterism means roughly the same biological effect with the same shape (isos = equal, steros = place, shape).
Since bioisosteria is usually based on a lock-and-key principle as with mimetics , the terms bioisosteric active ingredients and mimetics overlap .
When considering bioisosterism, the similarity between molecules and their functional groups with regard to their biological effect plays the greatest role. Alfred Burger defined bioisosteric active ingredients as follows:
"Compounds or groups of molecules with almost identical molecular shape and volume, as well as roughly the same distribution of electrons, which have similar physical properties."
This definition is more far-reaching than the approach of Langmuir (1919), which requires the same number and the same arrangement of electrons, and also includes Grimm's hybrid displacement law (1925). The isolobal concept (R. Hoffmann, Nobel Prize for Chemistry 1981) is based on a similar concept, which uses not only the number of electrons but also the shape and energy of the frontier orbitals of the molecular fragments to be compared.
A distinction is made between classic bioisosteres, which are sterically and electronically very similar (e.g. the halides -F, -Cl, -Br, -I, as well as the cyano group -CN, which each occupy a free bond) and non-classic bioisosteres. In the case of the latter, the exchanges can be much more complex, for example a cyclic structure (ring system) for an acyclic (open-chain radical).
The importance of bioisosteres becomes particularly clear against the background of metabolic and toxicological considerations. While a benzene ring is easily epoxidized , the bioisosteric methylthiophene group is metabolically more stable.
By exchanging a carboxylic acid group for a tetrazole ring, the bioavailability is significantly increased with a comparable acidity .
In this way, bioisosteric exchanges enable the fine-tuning of active ingredient properties. Prominent examples of this are the phosphodiesterase-5 inhibitors sildenafil and vardenafil , with the latter also being able to circumvent patent protection.
Ring-to-ring transformation
The ring-to-ring transformation refers to the exchange of one heterocyclic (or carbocylic) ring for another.
A benzene ring can be replaced by heterocycles such as thiophene, furan, pyrrole, selenophene, oxazole, thiazole, isaoxal, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, with thiophene having the greatest physicochemical similarity to benzene compared to the previously mentioned heteroaromatic compounds.
literature
- Carsten D. Siebert: The Bioisosteric Concept: Drug Development. In: Chemistry in Our Time . Volume 38, 2004, pp. 320-324, doi: 10.1002 / ciuz.200400331 .
- Hans-Joachim Böhm, Gerhard Klebe, Hugo Kubinyi: drug design. Spectrum Akademischer Verlag, 2002, ISBN 3-8274-1353-2 , pp 149–152. (Unchanged reprint of the 1st edition, 1996).
- Daniel Trachsel, David Lehmann, Christoph Enzensperger: Phenethylamine: from structure to function . Nachtschatten Verlag, Solothurn 2013, ISBN 978-3-03788-700-4 .
Individual evidence
- ↑ Otto-Albrecht Neumüller (Ed.): Römpps Chemie-Lexikon. Volume 3: H-L. 8th revised and expanded edition. Franckh'sche Verlagshandlung, Stuttgart 1983, ISBN 3-440-04513-7 , p. 1968.
- ^ Daniel Trachsel, David Lehmann, Christoph Enzensperger: Phenethylamine: from structure to function . Nachtschatten Verlag, Solothurn 2013, ISBN 978-3-03788-700-4 , p. 341 .