23707-33-7

Usage

Uses

Used in Pharmaceutical Industry:
Metrifudil is used as a therapeutic agent for targeting the A3 adenosine receptors. Its agonistic action on these receptors can lead to potential treatments for various diseases and conditions, including neurodegenerative disorders, inflammation, and certain types of cancer.
Used in Research Applications:
In the field of scientific research, Metrifudil is used as a research tool to study the role and function of A3 adenosine receptors in cellular processes and disease mechanisms. This helps researchers understand the underlying pathways and develop new therapeutic strategies for various conditions.
Used in Drug Development:
Metrifudil's selectivity for the A3 adenosine receptor makes it a valuable compound in the development of new drugs. It can be used as a lead compound or a reference in the design and synthesis of novel molecules targeting the A3 adenosine receptor for specific therapeutic applications.

InChI:InChI=1/C18H21N5O4/c1-10-4-2-3-5-11(10)6-19-16-13-17(21-8-20-16)23(9-22-13)18-15(26)14(25)12(7-24)27-18/h2-5,8-9,12,14-15,18,24-26H,6-7H2,1H3,(H,19,20,21)/t12-,14-,15-,18-/m1/s1

Upstream product

• 89-93-0 ortho-methylbenzylamine 
• 2004-06-0 6-Chloropurine riboside 

Relevant academic research and scientific papers

Preparation, biological activity and endogenous occurrence of N6-benzyladenosines

Cytokinin activity of forty-eight 6-benzyladenosine derivatives at both the receptor and cellular levels as well as their anticancer properties were compared in various in vitro assays. The compounds were prepared by the condensation of 6-chloropurine rib

SUBSTITUTION DERIVATIVES OF N6-BENZYLADENOSINE, METHODS OF THEIR PREPARATION, THEIR USE FOR PREPARATION OF DRUGS, COSMETIC PREPARATIONS AND GROWTH REGULATORS, PHARMACEUTICAL PREPARATIONS, COSMETIC PREPARATIONS AND GROWTH REGULATORS CONTAINING THESE COMPOU

The invention concerns novel substitution derivatives of N6-benzyladenosine having anticancer, mitotic, immunosuppressive and antisenescent properties for plant, animal and human cells. This invention also relates to the methods of preparation

Anti-HCV nucleoside derivatives

The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.

Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: Elucidation of a novel binding mode for a 2-Amino-N6-substituted adenosine

As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N6-, 2-amino-N6-, and N2-substituted adenosine analogues were synthesized and tested to establish structure - activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for N6-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N6-[2-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 μM. 2-[[2-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 μM. To explore the potential of an additive effect that having the N6 and N2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N6,N2-disubstituted adenosine analogues to yield N6-(2-phenylethyl)-2-[(2-phenylethyl)amino]adenosine (69) as a 30 μM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 A? X-ray structure of a T. brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this 'flipped and rotated' binding mode.

N-substituted adenosines as novel neuroprotective A1 agonists with diminished hypotensive effects

The synthesis and pharmacological profile of a series of neuroprotective adenosine agonists are described. Novel A1 agonists with potent central nervous system effects and diminished influence on the cardiovascular system are reported and compared to selected reference adenosine-agonists. The novel compounds featured are derived structurally from two key lead structures: 2- chloro-N-(1-phenoxy-2-propyl)adenosine (NNC 21-0041, 9) and 2-chloro-N-(1- piperidinyl)adenosine (NNC 90-1515, 4). The agonists are characterized in terms of their in vitro profiles, both binding and functional, and in vivo activity in relevant animal models. Neuroprotective properties assessed after postischemic dosing in a Mongolian gerbil severe temporary forebrain ischemia paradigm, using hippocampal CA1 damage endpoints, and the efficacy of these agonists in an A1 functional assay show similarities to some reference adenosine agonists. However, the new compounds we describe exhibit diminished cardiovascular effects in both anesthetized and awake rats when compared to reference A1 agonists such as (R)phenylisopropyladenosine (R-PIA, 5), N- cyclopentyladenosine (CPA, 2), 4, N-[(1S,trans)-2- hydroxycyclopentyl]adenosine (GR 79236, 26), N-cyclohexyl-2'-O- methyladenosine (SDZ WAG 994, 27), and N-[(2-methylphenyl)methyl]adenosine (Metrifudil, 28). In mouse permanent middle cerebral artery occlusion focal ischemia, 2-chloro-N-[(R)-[(2-benzothiazolyl)thio]-2-propyl]adenosine (NNC 21-0136, 12) exhibited significant neuroprotection at the remarkably low total intraperitoneal dose of 0.1 mg/kg, a dose at which no cardiovascular effects are observed in conscious rats. The novel agonists described inhibit 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate-induced seizures, and in mouse locomotor activity higher doses are required to reach ED50 values than for reference A1 agonists. We conclude that two of the novel adenosine derivatives revealed herein, 12 and 5'-deoxy-5'-chloro-N-[4-(phenylthio)-1- piperidinyl]adenosine (NNC 21-0147, 13), representatives of a new series of P1 ligands, reinforce the fact that novel selective adenosine A1 agonists have potential in the treatment of cerebral ischemia in humans.

Selective tight binding inhibitors of trypanosomal glyceraldehyde-3- phosphate dehydrogenase via structure-based drug design

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the sleeping sickness parasite Trypanosoma brucei is a rational target for anti- trypanosomatid drug design because glycolysis provides virtually all of the energy for the bloodstream form of this parasite. Glycolysis is also an important source of energy for other pathogenic parasites including Trypanosoma cruzi and Leishmania mexicana. The current study is a continuation of our efforts to use the X-ray structures of T. brucei and L. mexicana GAPDHs containing bound NAD+ to design adenosine analogues that bind tightly to the enzyme pocket that accommodates the adenosyl moiety of NAD+. The goal was to improve the affinity, selectivity, and solubility of previously reported 2'-deoxy-2'-(3-methoxybenzamido)adenosine (1). It was found that introduction of hydroxyl functions on the benzamido ring increases solubility without significantly affecting enzyme inhibition. Modifications at the previously unexploited N6-position of the purine not only lead to a substantial increase in inhibitor potency but are also compatible with the 2'-benzamido moiety of the sugar. For N6-substituted adenosines, two successive rounds of modeling and screening provided a 330-fold gain in affinity versus that of adenosine. The combination of N6- and 2'- substitutions produced significantly improved inhibitors. N6-Benzyl (9a) and N6-2-methylbenzyl (9b) derivatives of 1 display IC50 values against L. mexicana GAPDH of 16 and 4 μM, respectively (3100- and 12500-fold more potent than adenosine). The adenosine analogues did not inhibit human GAPDH. These studies underscore the usefulness of structure-based drug design for generating potent and species-selective enzyme inhibitors of medicinal importance starting from a weakly binding lead compound.

Purine derivatives

A compound of formula (I), or a pharmaceutically acceptable salt thereof: STR1 wherein X is hydrogen, amino, halogen, hydroxy, lower alkoxy or lower alkyl andR 1 is STR2 wherein Y is methylene or a valence bond, R 2 and R 5 is H or lower, straight or branched alkyl,R 3 is H or lower alkyl, orR 2 and R 3 can together form a cyclobutyl, cyclopentyl, cyclohexyl or phenyl ring,Z is oxygen, methylene, sulphur, sulphonyl or a valence bond,R 4 is H, lower alkyl, aralkyl, a mono or bicyclic aromatic system optionally substituted with various groups.The compounds have been found useful for treating central nervous system ailments.