Investigation of agents with indol skeleton was started in Richter Ltd. 50 years ago. This paper presents the results obtained by Richter's scientists. At first, a vasoactive alcaloid, vincamine was extracted from the leaves of Vinca minor in industrial quantity in 1955. This agent selectively improves the cerebral blood supply. Vincamine (Devincan) is used for the treatment of cerebrovascular disorders from 1959. Vinpocetine (Cavinton), the most powerful vasoactive compound was produced by transforming the chemical structure of vincamine. Cavinton is a cis(3S,16S)-derivate of vincamine having antianoxic, antiischaemic and neuroprotective properties. Therefore, it is frequently used in the therapy of cerebral disorders of vascular origin. Cavinton was introduced into clinical practice in 1978. At present, Cavinton tablets are approved in 47 countries. The third compound, vintoperol is a trans(3S,16R)-derivate of vincamine. Vintoperol proved to be a powerful enhancer of blood flow in the lower extremities. Because of its toxic side effects the agent is not used in clinical practice.

01 Jan 2000·Biological and Pharmaceutical BulletinQ4 · MEDICINE

Identification and Clearance Involved in the Formation of Glucuronides of RT-3003, a New Peripheral Blood Flow Enhancer, and Its Metabolite in Rats.

Q4 · MEDICINE

Article

Author: Harumi Uekusa ; Masataka Ishibashi ; Hiroyuki Yoshitsugu ; Takayuki Kaburagi ; Toshio Nanbo

Glucuronides of RT-3003 and its metabolite (9-OH-RT-3003), which was hydroxylated at the 9 position on the benzene ring, were separated by HPLC and identified by liquid chromatography (LC)/MS/MS and NMR. The conjugation sites of these glucuronides were determined by nuclear Overhauser effects (NOE) irradiation; RT-3003 was conjugated at an alcoholic hydroxyl group of the hydroxymethyl moiety, and 9-OH-RT-3003 at a phenolic hydroxyl group on a benzene ring and at an alcoholic hydroxyl group of a hydroxymethyl moiety. On a reversed-phase HPLC of 9-OH-RT-3003, alcoholic glucuronide was eluted later than phenolic glucuronide, indicating the high hydrophobicity of alcoholic glucuronide. Clearance for the glucuronidation (ClG) of RT-3003 was lower than the summation of ClG for two types of glucuronidation of 9-OH-RT-3003. ClG of 9-OH-RT-3003 was high in phenolic glucuronide. The activity of UDP-glucuronyltransferase (UDPGT) for RT-3003 was 9.63 times that for 9-OH-RT-3003, and the activity ratio of the two types of glucuronidation of 9-OH-RT-3003 was similar to the ratio of the corresponding ClG. The difference between ClG and UDPGT activity is discussed in association with clearance for the hydroxylation and interaction of substrates with UDPGT.

01 Oct 1999·Journal of Mass SpectrometryQ4 · CHEMISTRY

Key fragments for identification of positional isomer pair in glucuronides from the hydroxylated metabolites of RT-3003 (Vintoperol) by liquid chromatography/electrospray ionization mass spectrometry

Q4 · CHEMISTRY

Article

Author: Masataka Ishibashi ; Toshio Nanbo ; Noriko Kagi ; Tetsuo Fukuhara ; Hiroyuki Yoshitsugu

The mass spectral properties of glucuronides of the 9- and 10-hydroxylated metabolites of RT-3003 (Vintoperol; (-)-1beta-ethyl-1alpha-hydroxymethyl-1,2,3,4,6,7, 12balpha-octahydroindolo[2,3-a]quinolizine), which were fractionated by high-performance liquid chromatography with fluorescence detection, were investigated using the positive ion electrospray ionization mode. These glucuronides showed predominantly the protonated molecular ion ([M + H](+) ion), and the [M + H](+) ion provided a characteristic product ion spectrum in which abundant ions were obtained at m/z 301, 160 and 142. The first ion, corresponding to the [aglycone + H](+) ion, was produced by neutral loss of the glucuronic acid moiety from the [M + H](+) ion. The product ion spectrum of the [M + H](+) ion of hydroxy-RT-3003 revealed a number of ions common to the glucuronide spectra, suggesting that other two ions observed most likely represent fragmentation of hydroxy-RT-3003. In turn, these glucuronides were positional isomers with respect to the binding site of glucuronic acid. The structures of the isomer pairs were discriminated by the presence of the ion of m/z 318 or 336 in the product ion spectrum. These ions were produced by fission of the C-ring, the same as for the formation of the ions of m/z 160 and 142, as were observed in the product ion spectrum from the [M + H](+) ion of hydroxy-RT-3003. For the formation of these ions, an unusual fragmentation process was proposed, and these ion structures were supported by evidence from the accurate mass measurement data. Additionally, in the sulfates of hydroxylated metabolites, a similar product ion corresponding to the ion of m/z 336 found in the phenolic glucuronides was observed, and was applied for identification of the sulfate metabolites.

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Indication	Highest Phase	Country/Location	Organization	Date
Arterial Occlusive Diseases	Phase 2	JP	Takata Seiyaku Co., Ltd.	-
Peripheral Arterial Disease	Phase 2	-	Takata Seiyaku Co., Ltd.	-
Peripheral Arterial Disease	Phase 2	-	Chemical Works of Gedeon Richter Plc	-
Peripheral Vascular Diseases	Phase 2	JP	Takata Seiyaku Co., Ltd.	-

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