Exenatide analogue
阅读说明：本技术 一种艾塞那肽类似物 (Exenatide analogue ) 是由 周述靓 王鹏 邓岚 于 2019-09-25 设计创作，主要内容包括：本发明涉及医药合成领域,公开了一种艾塞那肽类似物。本发明所述艾塞那肽类似物,用于制备治疗疾病的药物组合物,所述药物组合物在制备治疗下述至少一种疾病的药物中的用途,所述疾病包括II型糖尿病、糖耐量受损、I型糖尿病、肥胖、高血压、代谢综合征、血脂异常、认知障碍、动脉粥样硬化、心肌梗塞、冠状动脉心脏病、心血管疾病、中风、炎性肠道综合征和/或消化不良或胃溃疡、肝纤维化疾病和肺纤维化疾病。(The invention relates to the field of medicine synthesis, and discloses an exenatide analogue. The exenatide analogue provided by the invention is used for preparing a medicine composition for treating diseases, and the application of the medicine composition in preparing a medicine for treating at least one of the following diseases, wherein the diseases comprise type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorder, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular diseases, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcer, hepatic fibrosis diseases and pulmonary fibrosis diseases.)
1. An exenatide analog of structural formula I:
AA1-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-
Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA2(R)-AA3
Structure I
AA1 in structure I is:
Wherein X 1 and X 2 are H,
or CH 3, CH (CH 3) 2, C (CH 3) 3, CH (CH 2 CH 3) 2, C (CH 2 CH 3) 3, CH (CH 2 CH 2 CH 3) 2, C (CH 2 CH 2 CH 3) 3, CH (CH 3)) 2, C (CH (CH 3)) 3, C (CH 3),
Or CH 2 CH 3, CH 2 CH (CH 3) 2, CH 2 C (CH 3) 3, CH 2 CH (CH 2 CH 3) 2, CH 2 C (CH 2 CH 3) 3, CH 2 CH (CH 2 CH 2 CH 3) 2, CH 2 C (CH 2 CH 2 CH 3) 3, CH 2 CH (CH (CH 3)) 2, CH 2 C (CH (CH 3)) 3, CH 3688C,
AA2 in structure I is Lys, or Dah, or Orn, or Dab, or Dap;
AA3 in structure I is NH 2, or OH;
R in the structure I is HO 2 C (CH 2) n1 CO- (gamma Glu) n2 - (PEG n3 (CH2) n4 CO) n5 -
Wherein: n1 is an integer from 10 to 20;
n2 is an integer from 1 to 5;
n3 is an integer from 1 to 30;
n4 is an integer from 1 to 5;
n5 is an integer from 1 to 5.
2. Exenatide analogue according to claim 1, comprising a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex of the analogue, a prodrug based on the compound, or a mixture of any of the above forms.
3. exenatide analogue according to claim 1 and claim 2 for the preparation of a pharmaceutical composition for the treatment of a disease.
4. the pharmaceutical composition according to claim 3, for use in the manufacture of a medicament for the treatment of at least one of type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcer, liver fibrosis diseases and pulmonary fibrosis diseases.
5. The pharmaceutical composition according to claim 4, for use in the preparation of a medicament for the treatment of delayed efficacy and/or prevention of exacerbation of type II diabetes.
6. The pharmaceutical composition of claim 6, for use in the preparation of a medicament for reducing food intake, reducing beta cell apoptosis, increasing islet beta cell function, increasing beta-cell mass, and/or restoring glucose sensitivity to beta cells.
7. Exenatide analog according to claim 1, comprising the analog for use in a method of regulating blood glucose in vivo.
Technical Field
The invention relates to an exenatide analogue and application thereof, wherein the analogue is a glucagon-like peptide-1 (GLP-1) analogue.
Background
Diabetes has become the third non-infectious disease after cardiovascular and cerebrovascular disease and tumor, and the World Health Organization (WHO) predicts: in 2030, the number of diabetic patients worldwide will exceed 3.6 hundred million, of which more than 90% are type II diabetes. GLP-1 is a secretive from intestinal tract L cell, it has effects of promoting insulin secretion, inhibiting release of glucagon, stimulating B cell proliferation of pancreatic island, inducing B cell regeneration of pancreatic island, preventing B cell apoptosis of pancreatic island, improving insulin sensitivity and increasing glucose utilization, etc., and plays an important role in the occurrence and development of type II diabetes. A patient with type II diabetes is impaired in an intestinal insulinotropic effect, and the increase amplitude of the GLP-1 concentration after meal intake is reduced compared with that of a normal person, but the effects of promoting insulin secretion and reducing blood sugar are not obviously impaired, so that the GLP-1 can be used as an important target point for treating type II diabetes, and meanwhile, the GLP-1 has glucose concentration dependence, and the blood sugar reduction characteristic is the basis and guarantee of clinical application safety, so that the worry that serious hypoglycemia of the patient can be caused by the existing diabetes treatment medicines and schemes is avoided, and the method has a wide application prospect in the field of diabetes treatment.
However, the clinical application of GLP-1 faces huge problems, the GLP-1 generated by a human body is very unstable and is very easy to be degraded by dipeptidyl peptidase IV (DPP-IV) in vivo, and the plasma half-life period of the GLP-1 is short, so that the clinical application of the GLP-1 is limited. Also, many type II diabetics are reluctant to administer daily injections, so there is great promise in developing safe and effective GLP-1 analogues that can be administered once a week.
Disclosure of Invention
the invention provides an exenatide analog and application thereof, wherein the analog is a glucagon-like peptide-1 (GLP-1) analog.
To achieve the above object, the present invention provides, in a first aspect, a compound of structure I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, a prodrug based on the compound, or any mixture thereof.
AA1-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-
Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA2(R)-AA3
Structure I
AA1 in structure I is:
Wherein X 1 and X 2 are H,
Or CH 3, CH (CH 3) 2, C (CH 3) 3, CH (CH 2 CH 3) 2, C (CH 2 CH 3) 3, CH (CH 2 CH 2 CH 3) 2, C (CH 2 CH 2 CH 3) 3, CH (CH 3)) 2, C (CH (CH 3)) 3, C (CH 3),
or CH 2 CH 3, CH 2 CH (CH 3) 2, CH 2 C (CH 3) 3, CH 2 CH (CH 2 CH 3) 2, CH 2 C (CH 2 CH 3) 3, CH 2 CH (CH 2 CH 2 CH 3) 2, CH 2 C (CH 2 CH 2 CH 3) 3, CH 2 CH (CH (CH 3)) 2, CH 2 C (CH (CH 3)) 3, CH 3688C,
AA2 in structure I is Lys, or Dah, or Orn, or Dab, or Dap;
AA3 in structure I is NH 2, or OH;
R in the structure I is HO 2 C (CH 2) n1 CO- (gamma Glu) n2 - (PEG n3 (CH2) n4 CO) n5 -
wherein: n1 is an integer from 10 to 20;
n2 is an integer from 1 to 5;
n3 is an integer from 1 to 30;
n4 is an integer from 1 to 5;
n5 is an integer from 1 to 5.
the invention also provides pharmaceutical compositions comprising a compound according to the invention and the use of a pharmaceutical composition comprising a compound of the invention for the preparation of a medicament for the treatment of a disease.
Preferably, the use of the pharmaceutical composition in the manufacture of a medicament for the treatment of at least one of type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcer, liver fibrosis diseases and pulmonary fibrosis diseases.
Preferably, the pharmaceutical composition is applied to the preparation of medicines for treating delayed drug effect and/or preventing worsening of type II diabetes.
Preferably, the use of the pharmaceutical composition for the manufacture of a medicament for reducing food intake, reducing beta cell apoptosis, increasing islet beta cell function, increasing beta cell mass, and/or restoring glucose sensitivity to beta cells.
the invention still further provides methods of administering the compounds to a subject for the modulation of blood glucose in vivo.
Further details of the invention are set forth below, or some may be appreciated in embodiments of the invention.
unless otherwise indicated, the amounts of the various ingredients, reaction conditions, and the like used herein are to be construed in any case to mean "about". Accordingly, unless expressly stated otherwise, all numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in the respective experimental conditions.
herein, when a chemical structural formula and a chemical name of a compound are ambiguous or ambiguous, the compound is exactly defined by the chemical structural formula. The compounds described herein may contain one or more chiral centers, and/or double bonds and the like, and stereoisomers, including isomers of double bonds (e.g., geometric isomers), optical enantiomers, or diastereomers, may also be present. Accordingly, any chemical structure within the scope of the description, whether partial or complete, including similar structures as described above, includes all possible enantiomers and diastereomers of the compound, including any stereoisomer alone (e.g., pure geometric isomers, pure enantiomers, or pure diastereomers), as well as any mixture of such stereoisomers. Mixtures of these racemates and stereoisomers may also be further resolved into the enantiomers or stereoisomers of their constituent members by those skilled in the art using non-stop separation techniques or methods of chiral molecular synthesis.
The compounds of formula I include, but are not limited to, optical isomers, racemates and/or other mixtures of these compounds. In the above case, a single enantiomer or diastereomer, such as an optical isomer, can be obtained by asymmetric synthesis or racemate resolution. Resolution of the racemates can be accomplished by various methods, such as conventional recrystallization from resolution-assisting reagents, or by chromatographic methods. In addition, the compounds of formula I also include cis and/or trans isomers with double bonds.
The compounds of the present invention include, but are not limited to, the compounds of formula I and all of their pharmaceutically acceptable different forms. The pharmaceutically acceptable different forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above and any mixtures of these forms.
The compound shown in the structure I provided by the invention has stable property, is not easily degraded by dipeptidyl peptidase IV (DPP-IV) in vivo, is a long-acting GLP-I analogue, and has a remarkable hypoglycemic effect.
Detailed Description
The invention discloses a glucagon-like peptide-1 (GLP-1) analogue and application thereof, and a person skilled in the art can realize appropriate improvement on related parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the process of the present invention has been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the compounds and processes described herein, as well as other changes and combinations of the foregoing, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
The Chinese names corresponding to the English abbreviations related in the invention are shown in the following table:
english abbreviation
name of Chinese
English abbreviation
Name of Chinese
Fmoc
9-fluorenylmethoxycarbonyl group
OtBu
Tert-butoxy radical
tBu
Tert-butyl radical
Boc
Boc-acyl
Trt
Trityl radical
Pbf
(2, 3-dihydro-2, 2, 4, 6, 7-pentamethylbenzofuran-5-yl) sulfonyl group
Ala
Alanine
Leu
Leucine
Arg
Arginine
Lys
Lysine
Asn
Asparagine
Met
Methionine
Asp
Aspartic acid
Phe
Phenylalanine
Cys
Cysteine
Pro
Proline
Gln
Glutamine
Ser
Serine
Glu
Glutamic acid
Thr
Threonine
Gly
Glycine
Trp
Tryptophan
His
histidine
Tyr
Tyrosine
Ile
Isoleucine
Val
Valine
Dap
2, 3-diaminopropionic acid
Dab
2, 4-diaminobutyric acid
Orn
Ornithine
Dah
2, 7-Diaminoheptanoic acid
Dhser
Dehydroxyserine
Dhthr
Dehydroxythreonine
Dhval
2, 3-didehydro valine
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