CN106963775A - Cucurbitacin L medicinal usage - Google Patents

Abstract

The present invention relates to cucurbitacin L or its pharmaceutically acceptable solvate and its be used as purposes of the therapeutic agent especially as inhibitors of dipeptidyl IV.

Description

Cucurbitacin L medicinal usage

Technical field

The present invention relates to pharmaceutical technology field, specifically, it is used as dipeptidyl peptidase the present invention relates to compound cucurbitacin L The medicinal usage of IV (DPP-IV) inhibitor.

Background technology

DPP IV (IUBMB enzyme nomenclature EC.3.4.14.5) is a kind of II types memebrane protein, in the literature with a variety of Title is referred to, including DPP4, DP4, DAP-IV, FAP β, ADCP 2, ABP (ADAbp), bis- peptidyls of Dipeptidylaminopeptidase IV, Xaa-Pro--aminopeptidase, Gly-Pro naphthyls amidase, rear proline (postproline) Dipeptidylaminopeptidase IV, lymphocyte antigen CD26, glycoprotein GP110, DPP IV, sweet ammonia Acyl Prolyl iminopeptidase, glycyl Prolyl iminopeptidase, X- prolyl pipeptidyl bases aminopeptidase, pep X, HLA CD26, glycylprolyl Dipeptidylaminopeptidase, two peptidyl-peptide hydrolases, glycylprolyl aminopeptidase, two peptidyls- Aminopeptidase IV, DPP IV/CD26, aminoacyl-prolyl pipeptidyl base aminopeptidase, T cell triggering molecule Tp103, X- PDAP.DPP IV is referred to herein as " DPP-IV ".

DPP-IV is a kind of non-classical serine aminopeptidase, and it is removed from the amino terminal (N- ends) of peptide and protein Remove Xaa-Pro dipeptides.Some naturally occurring peptides are also it has been reported that the DPP-IV dependences of X-Gly or X-Ser type dipeptides are slow Release.

The present invention relates to the change that can suppress dipeptidyl peptidase-IV (Dipeptidyl peptidase IV, DPP-IV) activity Compound and/or pharmaceutically acceptable solvate, this kind of compound can be used for treatment diabetes, such as diabetes B, high blood Sugar, metabolic syndrome, hyperinsulinemia, obesity, angiocardiopathy and abnormal such as atherosclerosis, cranial vascular disease, in Pivot nervous system disease is abnormal including schizophrenia, anxiety disorder, Bipolar depression, depression, insomnia, cognitive disorder, Gastrointestinal disease and exception, cancer, inflammation and inflammatory disease, respiratory disease and exception, skeletal muscle are abnormal, osteoporosis, more Term symptom or exception, periodontal disease such as gingivitis, and various immunoregulatory disorders.

DPP-IV belongs to serine peptide enzyme family, belong to together the family also have DPP2, DPP8, DPP9, FAP and POP etc..Animal model experiment result shows that such as anaemia, alopecia, decrease of platelet and splenomegaly can be caused by suppressing DPP8/9 Deng toxic reaction [Lankas GR, Leiting B, et al.Dipeptidyl peptidase IV inhibition for the treatment of type2diabetes:potential importance of selectivity over dipeptidyl peptidases8and9.Diabetes,2005,54:2988-2994].Therefore, for the single targets of DPP-IV The design and significant [Bhumika DP, the ManJunath DG.Recent of exploitation for the selective depressant selected approaches to medicinal chemistry and therapeutic potential of dipeptidyl peptidase-4(DPP-4)inhibitors.European Journal of Medicinal Chemistry,2014,74: 574-605], this is also the difficult point and key point of new selective DPP-IV inhibitor research and development.

Therefore, this area still needs the strong selective DPP-IV inhibitors of structure novelty, activity to meet clinical treatment Demand.

The content of the invention

DPP IV (Dipeptidyl peptidase IV, DPP-IV, CD26, EC 3.4.14.5) is a class energy The serine protease of specific for hydrolysis polypeptide or protein N-terminal Xaa-Pro or Xaa-Ala dipeptides.DPP-IV is atypia Serine protease, the Ser-Asp-His catalytic triads in its C-terminal region are different from typical serine protease, are backward Arrangement.DPP-IV is II type integral membrane proteins, is distributed widely in mammal and respectively organizes.DPP-IV is small in intestines, liver, kidney near-end Pipe, prostate, the differentiation surface epithelial cell of corpus luteum and leukocyte sub-type such as lymphocyte and Expression of Macrophages.Deposited in serum In DPP-IV soluble protein form, its 26S Proteasome Structure and Function is identical with embrane-associated protein form but lacks hydrophobic transmembrane structure Domain.

Diabetes B and fat attractive therapy can be turned into by suppressing DPP-IV.Although DPP-IV inhibitor energy The sugar tolerance of diabetes B patient is effectively improved, but the half-life period of many inhibitor is shorter, or toxicity is larger.Accordingly, it would be desirable to open Send out in pharmaceutical activity, stability, selectivity, toxicity, pharmacokinetics or medicine for characteristic more DPP-IV of advantage in terms of at least one Inhibitor is treated for diabetes B.Therefore, the invention provides a class novel DPP-IV inhibitors.

Embodiment

Following test example is for illustrating the present invention.

Compound cucurbitacin L (CAS used in the present invention:1110-02-7) obtained by mm Suppliers.

Biological assessment

Test example 1

The compounds of this invention is tested DPP-IV enzyme inhibition activities：

Instrument:

ELIASA, Envision (PerkinElmer, USA)

Material:

People source DPP-IV, is obtained to be expressed using baculovirus expression system in insect cell.

Substrate, Ala-Pro-AMC.

Process:

DPP-IV can the ultraviolet excitation production of specific for hydrolysis substrate A la-Pro-AMC generations product AMC, AMC through 355nm Fluorescent value linear change at 460nm wavelength in raw 460nm transmitting light, dynamic cooling water of units of measurement time, calculating obtains DPP4 activity. Experiment is used as control compound using MERK-0431.

Sample DMSO dissolves, Cord blood, and concentration controls of the DMSO in final system is not influenceing detection activity Within the scope of.

Compound MERK-0431 is that IC50 [nM] is 17.57 to DPP-IV inhibitory action.

Compound cucurbitacin L is 73.4% to DPP-IV inhibitory action when concentration is 20 μ g/mL.

Conclusion：Compound cucurbitacin L in the present invention has certain inhibitory action to DPP-IV enzymes.

The present invention can be summarized with others without prejudice to the concrete form of the spirit or essential characteristics of the present invention.Therefore, nothing By from the point of view of which point, the embodiment above of the invention can only all be considered the description of the invention and can not limit this hair It is bright.

Claims (1)

1. applications of the compound cucurbitacin L in DPP IV (DPP-IV) inhibitor medicaments are prepared.