ABSTRACT
A tetrahydropyran-based inhibitor (2) of mammalian ribonucleotide reductase (mRR) has been designed and synthesized based on the heptapeptide, N-AcFTLDADF (1), corresponding to the C-terminus of the R2 subunit of mRR. Inhibition studies revealed that 2 is indeed a competent inhibitor, albeit less potent than 1.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Pyrans/chemical synthesis , Ribonucleotide Reductases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Models, Molecular , Pyrans/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Gastrointestinal Motility/drug effects , Imidazoles/chemical synthesis , Nitriles/chemical synthesis , Acetylcholinesterase/metabolism , Animals , Blood Pressure/drug effects , Brain Chemistry/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Guinea Pigs , Histamine H2 Antagonists/chemical synthesis , Histamine H2 Antagonists/chemistry , Histamine H2 Antagonists/pharmacology , Ileum/drug effects , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacology , In Vitro Techniques , Male , Molecular Structure , Muscle Contraction/drug effects , Nitriles/chemistry , Nitriles/metabolism , Nitriles/pharmacology , Rabbits , Ranitidine/analogs & derivatives , Rats , Receptors, Histamine H2/metabolism , Sulfides/analysisABSTRACT
In a previous paper, we reported that a novel ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. In order to obtain more potent gastrointestinal motility enhancing agents than compound 2 and to examine the effects of various substituents both at a nitrogen atom (B) in the 2-imidazolidinylidene propanedinitrile moiety and a basic nitrogen atom (C), compounds 5-29 were synthesized and evaluated for acetylcholinesterase (AChE) inhibitory activity and potentiating action on electrically stimulated contractions of guinea pig ileum. Introduction of alkyl, benzyl, aryl or acyl groups to the nitrogen (B) or (C), remarkably influenced both activities. Among these, compounds 14 and 15 showed more potent AChE inhibitory activity (IC50 = 6.7, 6.8 nM, respectively) than compound 2 and were active in potentiating action on the ileal contraction (EC30 = 9.5, 11 nM, respectively) together with a negligible histamine H2-receptor blocking property. Furthermore, these compounds were found to be more effective in the enhancement of gastrointestinal motility in anesthetized rabbits than compound 2.
Subject(s)
Gastrointestinal Motility/drug effects , Imidazoles/pharmacology , Nitriles/pharmacology , Animals , Cholinergic Antagonists/pharmacology , Guinea Pigs , Histamine Antagonists , Ileum/drug effects , Imidazoles/chemistry , In Vitro Techniques , Male , Nitriles/chemistry , Rabbits , Ranitidine/chemistryABSTRACT
Ranitidine (1), the histamine H2-receptor antagonist, has been previously reported to increase gastric emptying and gastric motility by inhibition of acetylcholinesterase (AChE) and enhancement of acetylcholine (ACh) release. In order to obtain potent gastroprokinetic agents, a new series of ranitidine derivatives (5-32) possessing a nitrogen atom instead of a sulfur atom (B) was synthesized and their AChE inhibitory activity and potentiating action on electrically evoked contractions of guinea pig ileum were evaluated. Modification of substituents R1 and R2 markedly influenced the activities. In particular, compound 19, (1-[2-[[[5-(piperidinomethyl)-2-furanyl]methyl]amino]-ethyl]-2- imidazolidinylidene)propanedinitrile fumarate, showed 20 and 100 times more potent AChE inhibitory activity and potentiating action on the ileal contraction, respectively, than ranitidine. Furthermore, compound 19 (KW-5092) enhanced gastrointestinal motility in anesthetized rabbits along with a negligible histamine H2-receptor blocking activity.
