Synthesis of 2-imidazolidinylidene propanedinitrile derivatives as stimulators of gastrointestinal motility—III

Abstract

Recently, we reported that a ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. We have also found that introduction of substituents such as benzyl or 4-fluorobenzyl (i.e., giving 3 or 4) at the N-3 position of the moiety (A) significantly increased this activity. In this study, novel 2-imidazolidinylidene propanedinitrile derivatives possessing a thioether 5-15 were prepared and evaluated for in vitro assays; acetylcholinesterase (AChE) inhibitory activity and potentiating action on electrically induced contractions of guinea pig ileum. Compound 5, in which a nitrogen atom of compound 2 was replaced by a sulfur atom, was more potent than 2 in these tests. Also, in a series of thioether derivatives, introduction of substituents at the N-3 position of the 2-imidazolidinylidene propanedinitrile moiety markedly influenced both activities. In particular, compounds 12 and 13, which showed an excellent potency during in vitro study (AChE IC50 = 3.6 and 2.7 nM; ES. EC30 = 2.1 and 2.5 nM, respectively), were found to be more active in the enhancement of gastrointestinal motility in anesthetized rabbits than their corresponding parent compounds 3 and 4, respectively. In addition, compounds 12 and 13 showed lower affinity for the histamine H2-receptor than ranitidine. Therefore, these compounds may be potent and selective stimulators of gastrointestinal motility.

Digestibility and Bioavailability of the Active Components ofErica australisL. Aqueous Extracts and Their Therapeutic Potential as Acetylcholinesterase Inhibitors

“…One of the most promising approaches for treating this disease is to enhance the acetylcholine level in the brain using AChE inhibitors [ 22 ]. AChE activity is also related to intestinal motility and AChE inhibitors are administered to treat dysphagia, gastric stasis achalasia, abdominal pain, paralytic ileus, vomiting, and constipation [ 39 ]. Several plants belonging to the Ericaceae family have shown a very strong activity against AChE and BuChE [ 38 ]; however, to our knowledge, no previous studies had been reported for the infusions or decoctions of Erica species.…”

Antioxidant and anti-acetylcholinesterase activity of commercially available medicinal infusions after in vitro gastrointestinal digestion

“…Gut hydration is important in establishing a proper aqueous environment for the enzymatic digestion and absorption of nutrients, and to provide surface lubrication to propel intestinal contents by the peristaltic movements (Hirota and McKay, 2006). Conditions that may be associated with disturbances of the gastrointestinal motility and treated with AChE inhibitors include dysphagia, gastric stasis achalasia, abdominal pain, paralytic ileus, vomiting and constipation (Sasho et al, 1995).…”

“…The AChE inhibitor neostigmine is used to treat conditions related with impairment of gastrointestinal motility such as colonic pseudo-obstruction (Ponec et al, 1999) and post-operative impairment after colorectal surgery (Kreis et al, 2001). Other AChE inhibitors are also used to treat gastric motility dysfunctions such as metochlopramide and vinitidine (Sasho et al, 1995).…”

Small Molecule CXCR3 Antagonists

“…Three patents from Kyowa Hakko Kogyo and Millennium Pharmaceuticals claim imidazolidines as CXCR3 antagonists. − These compounds have their origins in a series of acetylcholine esterase inhibitors. − Data has been reported from screening at a single concentration in a radioligand binding assay with 125 I-CXCL10, which indicates that most compounds claimed in the patents have a pIC 50 of greater than 5.0 and provides some limited SAR. There is no conclusive evidence that either company still has an interest in the area, and there has been no further appearance of the compounds in the literature.…”