AG-041R, a novel indoline-2-one derivative, induces systemic cartilage hyperplasia in rats

Kitamura, Hidetomo; Kato, Atsuhiko; Esaki, Toru

doi:10.1016/s0014-2999(01)00957-8

Cited by 41 publications

(13 citation statements)

References 12 publications

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“…5 , decarboxylative couplings of N -Boc-Pro-OPht with N -alkyl- N -phenylalkacrylamides under the optimized reaction conditions provided the corresponding oxindoles in moderate yields. It is known that oxindoles widely occur in natural products with unique biological activity, and they are the privileged scaffolds for design and discovery of drugs 48 49 50 . Therefore, the present method affords a novel protocol for synthesis of oxindole derivatives.…”

Section: Resultsmentioning

confidence: 99%

Installing amino acids and peptides on N-heterocycles under visible-light assistance

Jin

Jiang

Wang

et al. 2016

Sci Rep

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Readily available natural α-amino acids are one of nature’s most attractive and versatile building blocks in synthesis of natural products and biomolecules. Peptides and N-heterocycles exhibit various biological and pharmaceutical functions. Conjugation of amino acids or peptides with N-heterocycles provides boundless potentiality for screening and discovery of diverse biologically active molecules. However, it is a great challenge to install amino acids or peptides on N-heterocycles through formation of carbon-carbon bonds under mild conditions. In this article, eighteen N-protected α-amino acids and three peptides were well assembled on phenanthridine derivatives via couplings of N-protected α-amino acid and peptide active esters with substituted 2-isocyanobiphenyls at room temperature under visible-light assistance. Furthermore, N-Boc-proline residue was successfully conjugated with oxindole derivatives using similar procedures. The simple protocol, mild reaction conditions, fast reaction, and high efficiency of this method make it an important strategy for synthesis of diverse molecules containing amino acid and peptide fragments.

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Section: Resultsmentioning

confidence: 99%

Installing amino acids and peptides on N-heterocycles under visible-light assistance

Jin

Jiang

Wang

et al. 2016

Sci Rep

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“…Oxoindoles bearing a tetrasubstituted carbon stereocentre at the 3-position are common motifs in natural products and in pharmaceutically interesting compounds. Chiral 3-amino-2oxoindoles are versatile and useful units for the preparation of pharmaceutically important lead compounds (Galliford & Scheidt, 2007;Dounay & Overman, 2003) and have been reported to be biologically active against a variety of targets, including anxiety and depression, examples being SSR149415 (Bernard et al, 2005), the gastrin CCK-B receptor agonist AG-041R (Kitamura et al, 2001) and the antimalarial agent NITD609 (Rottmann et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Four oxoindole-linked α-alkoxy-β-amino acid derivatives

et al. 2015

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Four structures of oxoindolyl α-hydroxy-β-amino acid derivatives, namely, methyl 2-{3-[(tert-butoxycarbonyl)amino]-1-methyl-2-oxoindolin-3-yl}-2-methoxy-2-phenylacetate, C24H28N2O6, (I), methyl 2-{3-[(tert-butoxycarbonyl)amino]-1-methyl-2-oxoindolin-3-yl}-2-ethoxy-2-phenylacetate, C25H30N2O6, (II), methyl 2-{3-[(tert-butoxycarbonyl)amino]-1-methyl-2-oxoindolin-3-yl}-2-[(4-methoxybenzyl)oxy]-2-phenylacetate, C31H34N2O7, (III), and methyl 2-[(anthracen-9-yl)methoxy]-2-{3-[(tert-butoxycarbonyl)amino]-1-methyl-2-oxoindolin-3-yl}-2-phenylacetate, C38H36N2O6, (IV), have been determined. The diastereoselectivity of the chemical reaction involving α-diazoesters and isatin imines in the presence of benzyl alcohol is confirmed through the relative configuration of the two stereogenic centres. In esters (I) and (III), the amide group adopts an anti conformation, whereas the conformation is syn in esters (II) and (IV). Nevertheless, the amide group forms intramolecular N-H···O hydrogen bonds with the ester and ether O atoms in all four structures. The ether-linked substituents are in the extended conformation in all four structures. Ester (II) is dominated by intermolecular N-H···O hydrogen-bond interactions. In contrast, the remaining three structures are sustained by C-H···O hydrogen-bond interactions.

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“…259 Additionally, AG-041R induced systemic cartilage hyperplasia by stimulation of chondrocyte proliferation and metabolism, an intrinsic property of this compound no related with its CCK 2 receptor antagonism. 260,261 AG-041R also stimulated the repair of osteochondrial defects in a rabbit model. 262 These findings suggest that this compound could be a therapeutic agent for cartilage disorders.…”

Section: K Indol-2-one-based Cck Antagonistsmentioning

confidence: 95%

“…Optimization of this substituent identified cyclopropylcarbonyl-methyl as the preferred one. When this substituent was combined with the introduction of acid groups into the aryl urea moiety, such as the thioacetic acid of compound 44, the CCK 2 receptor affinity was comparable to that of L-365, 260. 186 However, in vivo, the optimum compound of this series was the ethyl ester derivative 45 which showed potent inhibition of pentagastrin-induced gastric acid secretion in anaesthetized rats, with an ED 50 value of 0.06 mg/kg upon intraduodenal administration, being almost twice more potent that L-365,260 and YM022 in this assay.…”

Section: 5-benzodiazepine-based Cck 2 Antagonistsmentioning

confidence: 99%

Cholecystokinin antagonists: Pharmacological and therapeutic potential

Herranz

2003

Medicinal Research Reviews

168

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Cholecystokinin (CCK) is a regulatory peptide hormone, predominantly found in the gastrointestinal tract, and a neurotransmitter present throughout the nervous system. In the gastrointestinal system CCK regulates motility, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion. In the nervous system CCK is involved in anxiogenesis, satiety, nociception, and memory and learning processes. Moreover, CCK interacts with other neurotransmitters in some areas of the CNS. The biological effects of CCK are mediated by two specific G protein coupled receptor subtypes, termed CCK(1) and CCK(2). Over the past fifteen years the search of CCK receptor ligands has evolved from the initial CCK structure derived peptides towards peptidomimetic or non-peptide agonists and antagonists with improved pharmacokinetic profile. This research has provided a broad assortment of potent and selective CCK(1) and CCK(2) antagonists of diverse chemical structure. These antagonists have been discovered through optimization programs of lead compounds which were designed based on the structures of the C-terminal tetrapeptide, CCK-4, or the non-peptide natural compound, asperlicin, or derived from random screening programs. This review covers the main pharmacological and therapeutic aspects of these CCK(1) and CCK(2) antagonist. CCK(1) antagonists might have therapeutic potential for the treatment of pancreatic disorders and as prokinetics for the treatment of gastroesophageal reflux disease, bowel disorders, and gastroparesis. On the other hand, CCK(2) antagonists might have application for the treatment of gastric acid secretion and anxiety disorders.

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AG-041R, a novel indoline-2-one derivative, induces systemic cartilage hyperplasia in rats

Cited by 41 publications

References 12 publications

Installing amino acids and peptides on N-heterocycles under visible-light assistance

Installing amino acids and peptides on N-heterocycles under visible-light assistance

Four oxoindole-linked α-alkoxy-β-amino acid derivatives

Cholecystokinin antagonists: Pharmacological and therapeutic potential

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