Pharmacophor modification

Wu and Sun have presented a versatile procedure for the liquid-phase synthesis of 1,2, ,4-tctrahydro-/i-carbolines [77]. After successful esterification of the MeO-PEG-OH utilized with Fmoc-protected tryptophan, one-pot cyclocondensations with various ketones and aldehydes were performed under microwave irradiation (Scheme 7.68). The desired products were released from the soluble support in good yields and high purity. The interest in this particular scaffold is due to the fact that the l,2,3,4-tetrahydro-/f-carboline pharmacophore is known to be an important structural element in several natural alkaloids, and that the template possesses multiple sites for combinatorial modifications. The microwave-assisted liquid-phase protocol furnished purer products than homogeneous protocols and product isolation/ purification was certainly simplified. 

Sulfone-based y-secretase inhibitors including cyclohexane 45 (Ap IC50 = 3nM) have been reported [105]. Variations on this series include 3- and 4-substituted analogs such as 46 and 30, and highly potent bicyclic systems such as 47 (Ap IC50 = 0.06 nM), which was found to lower brain Ap in mice with an ED50 of 3.9mg/kg [106-108]. Piperidine sulfone 48 resulted from modification of hits from a pharmacophore-based computational search [109]. 

Structural modifications needed to alter VD generally need to alter physicochemical properties (e.g., lipophilicity, charge, etc.) which in turn alter other pharmacokinetic characteristics of the molecule and may not be tolerated by the pharmacophore of the target. 

Semisynthetic heterocycles are also important dmg molecules. These compounds attempt to capture the best of both worlds, being synthetic derivatives of natural products. The use of a natural product in the preliminary stages of the synthesis enables the elimination of numerous costly synthetic steps. The subsequent synthetic modifications enable further fine tuning of the natural product pharmacophore. There are a number of semisynthetic penicillin derivatives available. Similarly, there are also semisynthetic hormone analogs, especially of estrogens and gestagens. 

The above examples of peptide scaffold- or nonpeptide template-based peptidomimetic agonists or antagonists illustrate various strategies to elaborate bioactive conformation and/or pharmacophore models of peptide ligands at their receptors. In many cases, receptor subtype selectivity has also been achieved by systematic structural modifications of prototypic leads of peptidomimetics. Thus, although the 3D structures of G-protein-coupled receptors (GPCRs) remain as elusive (except for models constructed from homology-based low-... 

In many cases the isolated natural product may not be an effective drug for any of several possible reasons, but it may nevertheless have a novel pharmacophore. In such cases chemical modification of the natural product structure, either by direct modification of the natural product (semisynthesis) or by total synthesis, can often yield clinically useful drugs. Examples of this from the anticancer area are the drugs etoposide, teniposide, and topote-can, derived from the lead compounds podophyllotoxin and campothecin. 

In a lead refinement paradigm, one relies on empiricisms that are sometimes formalized in models such as QSARs and pharmacophores, or sometimes encoded in the mind of an experienced medicinal chemist. The compounds made in a lead refinement experiment tend to be even more focused on a given region of property space, and this may require different chemistries in order to access. The types of structural modifications suggested to be beneficial may not however be amenable to high-throughput chemistry, nor may the starting materials be available. 

Fig. 15.4 Performance assessment with ROC curves. The theoretical distributions for active (red curve) and inactive compounds (blue) as a function of their fit score on the pharmacophore (left). In most cases, these distributions overlap, leading to false predictions (colored areas). Upon threshold modification, proportions of such erroneous classifications change dramatically. Hence to any selection threshold S corresponds a unique...

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