Synthesis and biological evaluation of new antimuscarinic compounds with amidine basic centers. A useful bioisosteric replacement of classical cationic heads

Abstract

Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.

Characterization of Aclidinium Bromide, a Novel Inhaled Muscarinic Antagonist, with Long Duration of Action and a Favorable Pharmacological Profile

“…To reduce the potential for systemic side effects, muscarinic antagonists to treat respiratory diseases have been designed as quaternary ammonium salts administered by inhalation to minimize oral bioavailability and penetration of the blood-brain barrier (Cereda et al, 1990). Both local delivery to the lungs and low gastrointestinal absorption help to reduce systemic exposure and, therefore, lower the potential for side effects.…”

The Role of Formamidine Groups in Dextran Based Nonviral Vectors for Gene Delivery on Their Physicochemical and Biological Characteristics

“…The formamidine group, like all amidines, showed a strong basicity which lies between the values of tertiary amines and quaternary compounds. [ 26 ] The p K a of the dextran‐formamidine esters represented here is 10.1 as measured earlier by potentiometric titration. [ 23 ] In contrast to the tetrahedral amino moieties with located protons, amidines present a planar structure with delocalized charge.…”

Mass balance and metabolism of aclidinium bromide following intravenous administration of [14C]‐aclidinium bromide in healthy subjects

“…This is often achieved for inhaled therapies by simultaneous administration of oral and intravenous doses of the radiolabeled therapeutic agent to simulate the fate of the drug after inhalation. However, although the main portion of an aclidinium bromide dose is swallowed when administered by inhalation and is available for further hydrolysis in the gut [10], it is poorly absorbed by the oral route, like other quaternary ammonium salts [5,11]. Thus, intravenous administration of [ 14 C]-aclidinium bromide alone is sufficient to simulate the fate of inhaled aclidinium, facilitating evaluation of its mass balance and elucidation of its metabolic pathway.…”