CN107913274A - The medicinal usage of De Kalin alkali - Google Patents

Abstract

The title of the present invention is the medicinal usage of De Kalin alkali.Affiliated technical field is medical science.The technical problems to be solved by the invention are to be related to De Kalin alkali or its pharmaceutically acceptable solvate and its purposes as therapeutic agent especially as inhibitors of dipeptidyl IV.The main points of the technical solution of the technical problems to be solved by the invention are test of the compound to DPP IV enzyme inhibition activities.

Description

The medicinal usage of De Kalin alkali

Technical field

The present invention relates to pharmaceutical technology field, and specifically, the present invention relates to compound De Kalin alkali to be used as dipeptidyl peptidase The medicinal usage of enzyme 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 refers to, including DPP4, DP4, DAP-IV, FAP β, adenosine deaminase complex protein 2, adenosine deaminase binding protein (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, pepX, leukocyte antigen CD26, glycylprolyl Dipeptidylaminopeptidase, two peptidyl-peptide hydrolases, glycylprolyl aminopeptidase, two peptidyls- Aminopeptidase IV, DPPIV/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, 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 treating 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 or exception include 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 can cause such as anaemia, alopecia, decrease of platelet and splenomegaly the results show that 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 exploitation for the selective depressant selected are of great significance [Bhumika DP, ManJunath DG.Recent approaches to medicinal chemistry and therapeutic potential of dipeptidyl peptidase-4(DPP-4)inhibitors.European Journal of MedicinalChemistry,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 kind of 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 the soluble protein form of DPP-IV, 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 become 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.Therefore, it is necessary to open Hair has more the DPP-IV of advantage in pharmaceutical activity, stability, selectivity, toxicity, pharmacokinetics or medicine at least one aspect of characteristic Inhibitor is treated for diabetes B.Therefore, the present invention provides a kind of novel DPP-IV inhibitors.

Embodiment

Following test example is for illustrating the present invention.

Compound De Kalin alkali (CAS used in the present invention:54354-62-0) obtained by mm Suppliers.

Biological assessment

Test example 1

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

Instrument:

Microplate reader, 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 The transmitting light of raw 460nm, fluorescent value linear change at 460nm wavelength, is calculated DPP4 activity in dynamic cooling water of units of measurement time. Experiment is using MERK-0431 as control compound.

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

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

Compound De Kalin alkali is 85.7% to the inhibitory action of DPP-IV when concentration is 20 μ g/mL.

Conclusion：Compound De Kalin alkali in the present invention has good 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 cannot limit this hair It is bright.

Claims (2)

1. application of the compound De Kalin alkali in DPP IV (DPP-IV) inhibitor medicaments are prepared.

2. compound De Kalin alkali is not more than 85.7% when concentration is 20 μ g/mL to the inhibitory action of DPP-IV.