The novel biotransformation of an aminopyrrolidine to an aminopiperidine during the metabolism of 5-(4-chlorophenyl)-3-methyl-2-((2R)-2-(((1-methylethyl)amino)methyl)-1-pyrrolidinyl)-6-(4-pyridinyl)-4(3H)-pyrimidinone (AMG657417) was investigated using the NADPH-fortified S9 fraction from human liver. The major metabolite (M18) had a protonated molecule (MH(+) m/z 438) identical to that of AMG6...

In the liver microsome cyanide (CN)-trapping assays, piperazine-containing compounds formed significant N-methyl piperazine CN adducts. Two pathways for the N-methyl piperazine CN adduct formation were proposed: 1) The α-carbon in the N-methyl piperazine is oxidized to form a reactive iminium ion that can react with cyanide ion; 2) N-dealkylation occurs followed by condensation with formaldehyd...

In smokers, the primary pathway of nicotine metabolism is P450 2A6-catalyzed 5'-oxidation. The nicotine Delta(5'(1'))-iminium ion product of this reaction is further metabolized to cotinine by aldehyde oxidase. Previous investigators have reported kinetic parameters for cotinine formation using human liver cytosol as a source of aldehyde oxidase. Using [5-(3)H]nicotine and radioflow high-perfor...

Secondary phosphine oxides R2P(O)H are a relatively stable tautomeric form of secondary phosphinous acids R2P–OH that with imine/iminium species, or their donors, compounds P(O)–Csp3–N linkage (the phospha-Mannich reaction). These can be referred to as (α-aminoalkyl)phosphine oxides, (α-phosphinoylalkyl)amines, P(O),N-acetals. Compared P–Csp3–N linkages P,N-acetals, products reactions involving...