The synthesis and the pharmacol. evaluation of some new pyrazine-N-oxides I (R = H, Me, Et, n-Bu, benzyl) and analogs related to Acipimox, namely the corresponding carbinol and some of its ethers, are described.Some of these compounds showed strong antilipolytic activity in rats which was significantly long-lasting in the case of 2-methoxymethyl-5-methylpyrazine-4-oxide [83056-59-1].Structure-activity relations are discussed.

Isolation and identification of metabolites

Author: Caldwell, John ; Strolin-Benedetti, Margherita

A review.The metabolism of drugs and other xenobiotics in the mammalian body is in chem. terms, most generally a biphasic process,' with a first phase of a functionalization reaction of oxidation, reduction or hydrolysis, followed by a second phase of conjugation or biosynthesis.To a greater or lesser extent, there will occur excretion of the unchanged compound and of the unconjugated products of functionalization.In many cases, the compound itself may contain functional groups able to undergo conjugation directly, so that the final metabolites of a drug may include all of these various possibilities.The functionalization reactions serve to introduce or reveal functional groups within the drug mol.These reactions are most typically oxidations, notably hydroxylations; reductions and hydrolyzes also occur.In general, these reactions do not bring about dramatic changes to the physicochem. properties of drugs, a typical change being the oxidative demethylation of tertiary amines to secondary amines.However, aromatic hydroxylation introduces a phenolic hydroxy group, which may be ionized, and this will have a particular effect in the case of amines converted to phenolic amines, e.g. the 4-hydroxylation of amphetamine, which produces a zwitterionic phenolic amine markedly different from the parent drug.The hydrolysis of esters and amides may also cause significant changes to physicochem. properties.In comparison with the functionalization reactions, the conjugations produce very marked alterations to the physicochem. properties of the drug.The conjugations are biosynthetic reactions in which the drug, or one of its phase I metabolites, is linked with an endogenous conjugating agent.2 These are generally large, very polar mols., extensively ionized at physiol. pH, and are typified by glucuronic acid.5 Other examples of conjugations leading to increases in polarity and ionization include linkage with glutathione, glycine and other amino acids and sulfate ion, all of which serve to facilitate the elimination of the drug from the body.Contrasting with the above are two conjugation mechanisms which serve to 'mask' a particular functional group within the drug mol.These are: (i) methylation of phenols, largely exemplified by the action of catechol O-methyltransferase, which effectively terminates the biol. actions of noradrenaline and related catecholamines; and (ii) acetylation of amino groups, which may serve to reduce the formation of potentially toxic metabolites by N oxidation

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Indication	Highest Phase	Country/Location	Organization	Date
Lipid Metabolism Disorders	Phase 1	-	Pfizer Inc.	-

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