| Identification | Back Directory | [Name]
Luseogliflozin (hydrate) | [CAS]
1152425-66-5 | [Synonyms]
TS 071 hydrate
Luseogliflozin (hydrate)
(2S,3R,4R,5S,6R)-2-[5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl]-6-(hydroxymethyl)thiane-3,4,5-triol:hydrate | [Molecular Formula]
C23H32O7S | [MDL Number]
MFCD34574461 | [MOL File]
1152425-66-5.mol | [Molecular Weight]
452.56 |
| Hazard Information | Back Directory | [Description]
Luseogliflozin hydrate, which is an SGLT2 inhibitor approved in
Japan in March 2014 for the treatment of type 2 diabetes, was discovered
by Taisho Pharmaceutical and jointly developed and marketed
with Novartis as Lusefi®. Luseogliflozin selectively binds
and inhibits human SGLT2 with a Ki of 1.10 nM and IC50 value of
2.26 nM. | [Uses]
Luseogliflozin (TS 071) hydrate is a selective potent and orally active second-generation sodium-glucose co-transporter 2 (SGLT2) inhibitor with an IC50 of 2.26 nM. Luseogliflozin hydrate can be used for the research of type 2 diabetes mellitus (T2DM)[1][2]. | [Synthesis]
The most likely synthetic route capable of producing luseogliflozin
on process scale has been reported by Taisho. Commercially available 4-methoxy-
2-methyl-benzoic acid (160) was brominated in the presence
of a catalytic amount of iron powder, generating a 1:1 mixture of
3- and 5-bromo derivatives which were separable by recrystallization
from methanol to provide the desired regioisomer 161 in 34%
yield. Next, benzoic acid 161 was treated with oxalyl chloride to
give the corresponding acyl chloride 162, which underwent a Friedel¨C
Crafts reaction with ethoxybenzene (163) to afford 164 in 82%
yield for the two step sequence. The dibenzylic ketone 164 was
reduced using triethylsilane and boron trifluoride to give aglycon
165 in 99% yield. The Grignard reagent prepared from bromide
165 was then alkylated with thiolactone 166 (prepared from 5-
thio-D-glucose penta-O-acetate (169) as illustrated in Scheme 27)
to give rise to hemithioacetal 167 in 75% yield. This compound
underwent stereoselective reduction to provide thioglycoside 168
in 77% yield. Hydrogenation of 168 resulted in global debenzylation
to provide the desired product luseogliflozin (XIX) in 81%
yield.
The preparation of key thiolactone 166 started from 5-thio-Dglucose
penta-O-acetate (169) ; 169
could be prepared by eight steps from commercially available Dglucurono-
3,6-lactone. The anomeric acetyl group of 169
was selectively removed by hydrazine and acetic acid at room temperature
giving compound 170 in 70% yield. Subsequently, the
anomeric hydroxyl group of 170 was protected with tetrahydropyran.
Then, all acetyl groups of 171 were removed by Zempl¨|n
deacetylation, and the resulting hydroxyl groups of 172 were further
protected by benzyl groups using benzylbromide with sodium
hydride to generate 173. The tetrahydropyranyl group of 173 was
removed using pyridinium p-toluenesulfonate (PPTS), followed by
DMSO oxidation to provide 166 in 82% yield, by way of 174.
| [in vivo]
SGLT2 inhibition with Luseogliflozin (10 mg/kg/daily; oral gavage) significantly ameliorates hyperglycaemia, but not hyperinsulinaemia, in the OSI-906(45 mg/kg)-treated mice. Luseogliflozin ameliorates hyperglycaemia induced by OSI-906[2]. | Animal Model: | C57BL/6J male mice aged 8 weeks old[2] | | Dosage: | 10 mg/kg/daily | | Administration: | Oral gavage; for 7 days between 08:00 and 09:00 hours | | Result: | Treatment significantly ameliorated the OSI-906 (45 mg/kg)-induced hyperglycaemia. |
| [IC 50]
SGLT2 | [References]
[1] Anthony Markham,et al. Luseogliflozin: first global approval. Drugs. 2014 Jun;74(8):945-50. DOI:10.1007/s40265-014-0230-8
[2] Jun Shirakawa,et al. Luseogliflozin increases beta cell proliferation through humoral factors that activate an insulin receptor- and IGF-1 receptor-independent pathway. Diabetologia. 2020 Mar;63(3):577-587. DOI:10.1007/s00125-019-05071-w |
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Novachemistry
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https://www.novachemistry.com/ |
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