To increase lipophilicity

Many polar active molecules, selected through in vitro screening tests are unable to cross the biomembranes and their bioavailability is particularly low. Attaching a very lipophilic moiety can sometimes help to overcome this drawback. 

A typical example is given by the development of the anticonvulsant drug thiagabine starting from nipecotic 

Further developments demonstrated that the 4,4-diphenyl-3-butenyl moiety could be replaced by ether-type analogs and that the attachment of a lipophilic 3,3-diphenylpropyl side chain can take place at the carbon atom at the 6-position of the amino acid. However in this latter case, despite an reasonable in vitro activity (/C50 = 100 nM), no in vivo activity is observed. Final optimization of SKF 89976A led to the bis-thiophene tia-gabine. In a similar way, u),u)-diphenyl-alkyl chains (butterflies) were also attached to L-glutamic acid to yield glutamate metabotropic m3 receptor-selective agonists.  

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The H-site is formed of clusters ofnon-polar amino acid side chains which provide a highly hydrophobic surface, which, in the absence of a drug substrate is open to bulk solvent Binding of substrates to this site has been shown to relate to increased lipophilicity for substrates (4-hydroxyalkenes). The actual conjugation reaction, with the thiolate anion acting as a nucleophile proceeds via an SN2-type mechanism yielding the deactivated product... 

Organic extractants can be used to complex metal ions and to increase lipophilic-ity. The traditional metal extractants l-(2-pyridylazo)naphthol (PAN) and l-(2-thia-zolyl)-2-naphthol (TAN) have been used in polymer-based aqueous biphasic systems [43] and traditional solvent extraction systems [44]. These are conventional metal extractants widely used in solvent extraction appHcations. When the aqueous phase is basic, both molecules are ionized, yet they quantitatively partition into [HMIM][PF6] over the pH range 1-13. The distribution ratios for Fe, Co, and Cd (Figure 3.3-4) show that the coordinating and complexing abihties of the extractants are dependent on pH and that metal ions can be extracted from the... 

Monoamine oxidase (MAO) inactivates serotonergic and catecholanunergic neurotransmitters MAO (A and B) inhibitors exhibit mood elevatmg properties 5-FIuoro-OC-methyltryptamine (19) is an important MAO A-selective inhibitor In the treatment of certain depressive illnesses, 4-fluorotranylcypromine (20b) is 10 tunes more potent than the parent tranylcypromine (TCP, 20a) The enhanced in vivo activity may be due to increased lipophilicity of 20b and/or to blockade of metabolic para hydroxylation [52]... 

Betamethasone valerate and beclometasone dipropionate both mask the polar hydroxyl groups to increase lipophilicity. This increases the topical penetration for topical formulations used in eczema and psoriasis and aerosol formulations used in asthma. The log P0ctanoi/PH7 value of betamethasone is 2.01, whereas the log P0ctanoi/PH7 value f°r betamethasone (as valerate) is 3.60. 

Matile reported poor bilayer solubility of rigid-rod 9 so tackled this problem by incorporating lateral propylene side chains.35c This was expected to increase lipophilicity and also to improve the flexibility of the hydroxyl groups thus facilitating proton transport by the HBC mechanism. The structural modifications did not appear to have a detrimental effect on the active structure and increased ion flux rates were seen for the propylene-substituted oligo(phenylenes). 

A variety of proteins are acylated by formation of thioesters to cysteine and esters to serine and threonine. Acylation may serve either to anchor the proteins in membranes (e.g., rhodopsin Section 2.3.1) and the mannosidase of the Golgi, or to increase lipophilicity and thus enhance the solubilization of lipids being transported (e.g., the plasma apolipoproteins and milk globule proteins). Proteolipids with fatty acids esterified to threonine residues occur in the myelin sheath in nerves. 

The ot-acyloxylalkyl esters have also been extended to include the phosphate group, phosphonic acids, and phosphinic acids. One such example is fosinopril (57), an ACE inhibitor, where the phosphinic acid is O-a-acyloxyalkylated to increase lipophilicity to provide better absorption. 

C. Acetylenic series VI. EFFECTS OF THIOLS A. To increase lipophilicity... 

Frankild et al. [114] demonstrated that increasing the concentration of SLS augments the quantity of nickel in epidermal receptors. The build-up of nickel was ascribed to the effect of SLS on nickel s binding capacity in the epidermis. An analogous relationship, however, was not appreciated with hydrocortisone until the concentration of SLS was increased to 10 %, suggesting unresponsiveness of damaged skin to increasing lipophilicity. 

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