Solubility isosterism

Amino-3-methyl-l,2,4-thiadiazole has a relatively high melting point and low solubility in water, compared with that of the 3-ethyl homolog and the parent compound the isosteric 4-aminopyrimidines show a parallel behavior (see Table VT).6 5-Amino-3-methoxy-l,2,4-thiadiazole melts at a higher temperature than does the ethoxy homolog.83... 

The solubility coefficients of gases in glassy polymers are not constant, but decrease with increasing concentration of the gas in the polymers (2). Calculations of the isosteric enthalpy of sorption in several gas-polymer systems confirm that the gas-polymer affinity is reduced with increasing sorbed gas concentrations (24, 25, 26). The change in the isosteric enthalpy of sorption is a result of the changes in the polymer matrix induced by the presence of the sorbed gas. 

Further modification on 2 at P1( P/, and IV led to several hydroxy ethylene isosteres (e.g., 6 and 7),12-14 which displayed poorer enzyme inhibitory and antiviral potencies than 2 (Table 24.1). Incorporation of the constrained 3-S-tetrahydrofuranyl urethane in place of the (V-term in us acyclic tert-butyl urethane in 2 resulted in a remarkable 10-fold increase in enzyme inhibitory potency (IC50 <0.03 nM) and more than 100-fold increase in antiviral potency (CIC95 = 3 nM).15 Although very potent, the optimized inhibitors of the hydroxy ethylene isostere series still lacked adequate aqueous solubility and acceptable pharmacokinetic profile (Figure 24.2). 

The term isosterism has been used widely to describe the selection of structural components—the steric. electronic, and solubility characteristics that make them interchangeable in drugs of the same pharmacological class. The concept... 

Clusters of group-14 elements usually form soluble ions in salts with large cations [e.g. [K-crypt]+ complexes).Of the many possible clusters only the five-, nine-, and ten-atom units have been structurally characterized (Table 2). Homoatomic tetrahedral units have been found only in Zintl phases. Discrete tetrahedral E4 clusters are isosteric with P4 these are listed in Table 3. A nine-atom representative has recently been characterized in the A4Ge9 (A = Rb, Cs) Zintl phases. In the A12E17 (E = Ge, Sn) phases four- and nine-atom clusters are present in the same compound (see below). 

In the recent past, receptors and drug-reeeptor interaetions theories have highlighted the importance of physical and chemical characteristics with regard to drug action. Such salient features may include partition coefficients, solubility, degree of ionization, isosterism and bio-isosterism, surface activity, thermodynamic activity, intramolecular and intermolecular forces, redox potentials, stereochemisty and interatomic distances between various funetional groups. 

The replacement of the scissile peptide bond between the o-ala residues by a less reactive thioamide bond (332) [186], or by a non-hydrolysable reduced isostere (e.g. 333a [173] or 333b [187]), did not lead to an inhibitor of the soluble D,D-peptidases. 

The predominant form of monoglyceride present in intestinal content during fat digestion is the 2-isomer, which is unstable, slowly isomerizing to the 1-isomer. Few studies have compared the physical properties of the 1-and 2-isomers, but glyceryl monoethers, which are nearly isosteric and should have fairly similar physical properties, are prepared without difficulty. It would seem both feasible and interesting to examine the phase equilibria as well as molecular solubility of glyceryl 1- and 2-monounsaturated ethers. 

The substitution of phenyl ring with pyridine is widely used to improve metabolic stability. One efficient example of this can be recently found in HIV-1 inhibitors developed at Bristol-Myers Squibb and currently in clinical development. Compound 2 (Figure 2.5) was identified as lead in the discovery of drugs that inhibit the attachment of HIV to CD4 host cells but, due to high metabolism and low solubility, isosteres of the phenyl ring were evaluated. This led to the identification of BMS-488043 (Figure 2.5), which retained potency against HIV-1 attachment, but had better pharmacokinetic profile than compound 2 and was thus advanced in clinical trials [15]. 

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