Lipophilicity bioisosteric replacement

Bioisosteric replacement can be made from a position of knowledge, if the desirable properties of the substituent or substructure to be changed have been characterized. Such properties can include (with typical parameters) (a) size (volume, molar refractivity, surface area, Taft s) (b) shape (Verloop length and breadth, bond angles, interatom distances) (c) lipophilicity (log P, tt,/) (d) solubility (log S) (e) ionization state (pKg, a) ... 

A recent example of bioisosteric replacement of a carbon atom with silicon was reported by Warneck and colleagues at Paradigm Therapeutics, who synthesized the silicon derivative of the p38 MAP kinase inhibitor BIRB-796 (Figure 2.4), which is in clinical evaluation for several inflammatory diseases, such as rheumatoid arthritis, Crohn s disease, and psoriasis [14]. This silicon isostere, compound 1, was found to be unusually less lipophilic than BIRB-796, of comparable potency, and more metabolically stable in human hver microsomes. 

No two substituents are exactly alike. Any substitution impacts size, shape, electronic distribution, lipophilicity, pKa, chemical reactivity, susceptibility to metabolism, and the like. The bioisosteric approach is the total change induced by substituent replacement on the potency, selectivity, duration of action, bioavailability and toxicity, of an agrochemical. The following groups are examples of... 

In the losartan molecule, the substituted imidazole moiety is attached to the typical tetrazolyl-diphenyl unit (Figure 19.15). In practicing analog synthesis, the Novartis scientists conserved unchanged this latter part of the molecule but tried to prepare a bioisosteric equivalent of the substituted imidazole possessing similar interaction possibilities. The lipophilic n-butyl chain was maintained, the CN dipole was replaced by a CO dipole, and the ensemble chlorine substituent plus two imidazolic carbon atoms was replaced... 

The synthesis of ferrocene in 1951 by Pauson [86] followed by the elucidation of its structure by Wilkinson et al. [87] and Fischer and Pfab [88] constitutes a significant advance in modern chemistry. Indeed this time period, 1951-1952, marks the beginning of the explosion in transition metal organometallic chemistry. Ferrocene possesses an external structure that resembles that of an aromatic nucleus, it can be easily functionalized, is stable in a nonoxidizing environment, and is consequently well adapted to play the role of substituent in medicinal chemistry [89]. Besides this, it is also lipophilic and compact, and does not fundamentally modify the pharmacological properties of the molecule when it replaces a phenyl unless there are important bioisosteric considerations. In addition, it is not particularly toxic, with oral and LD50 values of 1320 and 500 mg/kg for rat and 832 and 335 mg/kg for mouse [90]. 

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