Chirality optimized receptors

Yamada et al. also prepared a series of stereoisomers of tris(2-pyridyl-methyl)amines 17 by combining Hpase-catalyzed optical resolution and Sn2-type replacement reaction [23]. When their log Ki values for Eu complexes were compared, im- and mono-substituted tripodes 17a and 17b gave larger log Ki values than both diastereomers of disubstituted tripodes 17c (Table 1). Although each tripode had three pyridine and one tertiary nitro- 

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Unlike desferrioxamine analogs designed for specific therapeutic purposes described above, chiral DFO analogs that form conformationally unique complexes with iron(lll) were designed to serve as chemical probes of microbial iron(lll) uptake processes. As mentioned above, ferrioxamine B can form a total of five isomers when binding trivalent metal ions, each as a racemic mixture. Muller and Raymond studied three separate, kinetically inert chromium complexes of desferrioxamine B (N-cis,cis, C-cis,cis and trans isomers), which showed the same inhibition of Fe-ferrioxamine B uptake by Streptomyces pilosus. This result may indicate either that (i) ferrioxamine B receptor in this microorganism does not discriminate between geometrical isomers, or that (ii) ferrioxamine B complexes are conformationally poorly defined and are not optimal to serve as probes. 

The shape of a drug molecule must be such as to permit binding to its receptor site. Optimally, the drug s shape is complementary to that of the receptor site in the same way that a key is complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so... 

The above narrative exemplifies a successful lead identification story, ensued by a successful lead optimization that led to the discovery of the FDA-approved drug vorapaxar. The original hit (2) was a racemic synthetic analog of himbacine, a natural product that has no thrombin receptor activity. Had we made this analog in the absolute chirality of himbacine, we would have missed the hit, since the thrombin receptor antagonist activity is exclusive to the unnatural e t-him-bacine series. The lead optimization efforts encountered several obstacles, as highlighted by the discontinuation of two recommended candidates. Within the project, we had to return several times to secondary lead generation and optimization in order to address the liabilities such as liver enzyme induction and sub-optimal mass balance that we encountered in the development candidates. 

Many examples of peptidocalixarenes and peptidoresorcinarenes show a natural tendency of peptidic backbones to form arrays of self-complementary hydrogen bonds that is often perceived as a disadvantage in constmction of chiral receptors. However, such arrays, when rationally optimized, can be of great significance for formation of supramolecular aggregates of finite or infinite sizes. For example, calix[4]arenes 16-25 with two peptides mounted on the same scaffold using... 

The principal alarm pheromone of Atta texam is (5)-(-l-)-4-methyl-3-heptanone (386a, Scheme 68) (173). Determination of threshold levels of both enantiomers showed that the naturally occurring (-t-) enantiomer was about 100 times more active than the (—) enantiomer (173, 312). It was also established that the (—) enantiomer did not inhibit response to the (-t-) enantiomer. However, the (—) enantiomer contained 1.3% of the (-h) enantiomer, so it is not possible to determine whether the (—) form has some slight activity of its own or not. It was concluded that the receptors on this ant must be chiral and respond maximally to the naturally occurring enantiomer. Pogonomyrmex barbatus, which also uses 4-methyl-3-heptanone as an alarm pheromone (313), responds to the 5-(-t-) enantiomer up to 10 times more than the / -(-) enantiomer (314). It is not known which enantiomer is synthesized by this ant, but we would propose, as a general rule, that an organism responds optimally to its own enantiomer or ratio of enantiomers. 

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