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CN-122010981-A - GLP-1 receptor agonism/GLP-1 secretagogue double-target compound

CN122010981ACN 122010981 ACN122010981 ACN 122010981ACN-122010981-A

Abstract

The invention relates to the design, preparation and application of a double-target compound with activity on both a human glucagon-like peptide-1 receptor (GLP-1R) and a KCNH6 potassium channel. The compounds exert dual actions of a GLP-1 receptor agonist and an endogenous GLP-1 secretagogue by activating GLP-1R and blocking KCNH6, and can be used for treating obesity, type 2 diabetes and related complications thereof.

Inventors

  • YANG JINKUI
  • LI YU
  • Request for anonymity

Assignees

  • 仁奎医药科技(北京)有限公司

Dates

Publication Date
20260512
Application Date
20241111

Claims (6)

  1. 1. A method and concept for designing a drug represented by the general formula (I). By combining human glucagon-like peptide-1 receptor (GLP-1R) agonism and KCNH6 potassium channel inhibition, dual-target synergistic efficacy of GLP-1 receptor agonists with endogenous GLP-1 secretagogues is exerted. Comprising GLP-1 receptor agonism/GLP-1 secretagogue dual-target compounds acting on GLP-1R and KCNH6 utilizing single chemical structural entities constructed by various methods; (I)
  2. 2. The compound of claim 1, wherein the "GLP-1R agonizing" moiety is independently agonizing GLP-1R. The "GLP-1R agonism" moiety of the compound includes, but is not limited to, structures of the following formulas (II) and (III), and the claims also include isomers and deuterated products of formulas (II) and (III): (II) (III) the chemical structures R1 and R2 in the general formula (II) can be independently or jointly Linker access sites Wherein the X moiety may comprise the following structure: ; wherein the Y moiety may comprise the following structure: ; the Y1 moiety comprises a benzene ring of any one structure of a five-membered ring, a six-membered ring, or a substituted benzene ring (containing a combined structure including any one or more of methyl, ethyl, hydroxyl, amino, mercapto, fluorine, chlorine, bromine), or a pyridine ring, or an aliphatic five-membered ring, or an aliphatic six-membered ring, or a nitrogen-oxygen-containing five-, six-, seven-membered aliphatic heterocyclic ring, including but not limited to the following representative structures: ; The Y2 moiety comprises: ; The chemical structures R1 and R2 in the general formula (II) can be independently or jointly Linker access sites.
  3. 3. The compound of claim 1, wherein the "Linker" moiety of the compound includes, but is not limited to, the following structure, or any structural group consisting of the following structures; Such as units consisting of ethylene glycol structure: ; or a unit consisting of a fatty chain: ; Or units consisting of unsaturated chains: ; or carboxylic acid: ; Or a unit consisting of an aromatic compound: ; or heteroatom-containing units such as sulfur, nitrogen, phosphine, etc., including but not limited to the following fragment units: ; R in the heteroatom-containing units may independently be: R in the heteroatom-containing unit is independently alkyl, alkoxy or hydrogen; Preferably, the alkyl is specifically methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl, and the alkoxy is-OEt and-OMe; in particular, the Linker may be composed of a plurality of glycosyl groups such as monosaccharides, disaccharides, or a polypeptide composed of a single amino acid, a dipeptide, and a plurality of amino acids.
  4. 4. The compound of claim 1, wherein the "KCNH6 inhibiting" moiety independently inhibits KCNH6. The compounds include, but are not limited to, structures of the following general formulas (IV) and (V): (IV) r1, R2, R3 and R4 can be respectively and independently or jointly any structure including methoxy, ethoxy, alkyl with the length of 1-5, amino, carboxylic acid and the like; Such as units consisting of ethylene glycol structure: ; or a unit consisting of a fatty chain: ; Or units consisting of unsaturated chains: ; Or a unit consisting of an aromatic compound: ; or heteroatom-containing units such as sulfur, nitrogen, phosphine, etc., including but not limited to the following fragment units: ; R in the heteroatom-containing units may independently be: R in the heteroatom-containing unit is independently alkyl, alkoxy or hydrogen; Preferably, the alkyl is specifically methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl, and the alkoxy is-OEt and-OMe; r1, R2 and R3 and R4 may independently or together form a ring structure, such as: 、 、 ; Linker interface part can also exist on aromatizing entity, also can exist on R1, R2, R3, R4 part; In particular, the KCNH6 inhibiting moiety of the structure includes various salt forms of the general formula (IV), such as quaternary ammonium salt forms of various anionic structures such as chloride, bromide, iodide, sulfate, etc.: the molecular structure of claim as shown in formula V: (V) wherein P, Q, R may be linked to the linker independently or together or in combination: P may be configured as a chemical entity attached to the V parent structure through an amide linkage, including but not limited to the following structures: P may be N is 0 to 10 in length P may be N is 1-5 in length P may be ; The L1 part can be any structure including methoxy, ethoxy, alkyl with the length of 1-5, amino, carboxylic acid and the like respectively and independently or jointly; Such as units consisting of ethylene glycol structure: ; or a unit consisting of a fatty chain: ; Or units consisting of unsaturated chains: ; Or a unit consisting of an aromatic compound: ; or heteroatom-containing units such as sulfur, nitrogen, phosphine, etc., including but not limited to the following fragment units: ; P may be ; The L2 part can be any structure including methoxy, ethoxy, alkyl with the length of 1-5, amino, carboxylic acid and the like respectively and independently or jointly; Such as units consisting of ethylene glycol structure: ; or a unit consisting of a fatty chain: ; Or units consisting of unsaturated chains: ; Or a unit consisting of an aromatic compound: ; or heteroatom-containing units such as sulfur, nitrogen, phosphine, etc., including but not limited to the following fragment units:
  5. 5. According to claim 4, the compound "KCNH6 moiety" may also have a tertiary amine structure obtained by reducing the quaternary ammonium salt structure in the above general formula (IV), as shown in general formula (VI): (VI) r1, R2, R3 and R4 can be respectively and independently or jointly any structure including methoxy, ethoxy, alkyl with the length of 1-5, amino, carboxylic acid and the like; Such as units consisting of ethylene glycol structure: ; or a unit consisting of a fatty chain: ; Or units consisting of unsaturated chains: ; Or a unit consisting of an aromatic compound: ; or heteroatom-containing units such as sulfur, nitrogen, phosphine, etc., including but not limited to the following fragment units: ; R in the heteroatom-containing units may independently be: R in the heteroatom-containing unit is independently alkyl, alkoxy or hydrogen; Preferably, the alkyl is specifically methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl, and the alkoxy is-OEt and-OMe; r1, R2 and R3 and R4 may independently or together form a ring structure, such as: 、 、 ; linker interface part can also exist on aromatizing entity, also can exist on R1, R2, R3, R4 part; In particular, the KCNH6 inhibiting moiety is configured to include various salt forms of formula (VI), such as hydrochloride, silver nitrate, hydrogen bromide, sulfate, and the like; the claims, also include deuterated drug structures formed by single or multiple substitutions in the above structures and stereoisomeric chiral undeployed mixtures and corresponding pharmaceutically acceptable salts formed by engineering chemical stereoconformations; The chemical structural entity of claim comprising the following chemical structures and related deuterated drug structures formed by single or multiple substitutions and stereoisomeric chiral undeployed mixtures and corresponding pharmaceutically acceptable salts formed by engineering chemical stereochemical conformations.
  6. 6. A compound selected from table 1: table 1.

Description

GLP-1 receptor agonism/GLP-1 secretagogue double-target compound Technical Field The application relates to the technical field of pharmaceutical chemistry, but is not limited to, and in particular relates to the design, preparation and application of a double-target compound with activity on both a human glucagon-like peptide-1 receptor (GLP-1R) and a KCNH6 potassium channel. Background The prevalence of diabetes continues to rise over the past few decades. The risk of cardiovascular diseases of people suffering from diabetes is two to four times higher than that of normal people, and serious consequences such as blindness, amputation, renal failure and the like can be caused, so that the people suffering from diabetes become important public health problems. Currently there are two major forms of diabetes, type 1 and type 2. The main causative agent of type 1 diabetes is that the human immune system attacks the beta cells of the islets, resulting in dysfunction of insulin secretion. Type 2 diabetes is the most common form of diabetes, accounting for about 90% of all diabetes, and is mainly associated with insulin resistance as opposed to insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin responsible for glucose balance, secreted by intestinal epithelial L cells, exerting a physiological effect by binding to its receptor. GLP-1 hyposecretion is also one of the pathogenesis of type 2 diabetes. The GLP-1 receptor (GLP-1R) belongs to the G protein-coupled receptor subfamily, and when GLP-1 binds to GLP-1R, it induces a series of biological effects. Currently, polypeptide drugs such as exenatide, liraglutide, semraglutide and the like based on GLP-1 analogues are widely applied to type 2 diabetics and simple obesity patients, and have the advantages of obviously reducing weight and improving glucose tolerance, protecting heart and kidney functions and the like. Because GLP-1 analogs need to be administered by subcutaneous injection and are often accompanied by gastrointestinal adverse reactions such as nausea and vomiting, oral administration of non-peptide small molecule GLP-1 receptor agonists has become a hotspot for the development of new drugs. Some non-peptide small molecule agonists have been introduced into the clinical trial phase, including Danuglipron developed by the company of pyroxene, orforglipron developed by the company of Gift, and HRS-7535 developed by the company of Henry. However, no small molecule GLP-1 receptor agonist is currently available for clinical use. Meanwhile, long-term use of GLP-1 receptor agonists can cause reduction of basal metabolic rate, further cause reduction of energy consumption and rebound of body weight, and still remain an important problem to be solved in the field. The human delayed rectifier potassium channel (KCNH 6) is a repolarized potassium channel. Research shows that the medicine acting on the KCNH6 channel in intestinal canal can obviously improve sugar tolerance, promote GLP-1 secretion, increase insulin sensitivity, and simultaneously does not influence the function of KCNH6 channel in heart. The present invention therefore aims to find novel compounds that are active on both GLP-1R and the intestinal KCNH6 channel, in particular with good biological properties, which can be safely applied in humans. The compound provided by the invention can play a role of a GLP-1 receptor agonist and an endogenous GLP-1 secretagogue by activating a GLP-1 receptor and blocking a KCNH6 potassium channel, and can be used for treating obesity, type 2 diabetes and related complications (shown in figure 1). Disclosure of Invention The invention provides a molecular structure of a compound function definition shown in a general formula (I), which comprises the function of realizing GLP-1R agonism and KCNH6 double-target inhibition activity, and the two parts have synergistic effect. GLP-1R and KCNH6 together form a single drug molecular structure. These compounds are active on both GLP-1R and KCNH6 channels. The invention also relates to a pharmaceutical composition containing the compounds and application of the compounds in medicines for treating diseases such as diabetes and the like. (I) The invention aims to protect the drug design concept and the realized drug design entity which realize GLP-1R agitation and KCNH6 inhibition and synergistically exert the effects of reducing blood sugar and losing weight through reasonable chemical bonds and modes. The invention discloses a drug design method and concept for synergistically exerting the effects of losing weight and reducing blood sugar by combining GLP-1R agonism and KCNH6 inhibition. Comprises constructing a drug design of GLP-1R and KCNH6 double-target double-mechanism synergistic hypoglycemic by utilizing various methods. The compounds of the invention have a molecular structure that is constructed by combining a "GLP-1R agonism" moiety and a "KCNH6 inhibition". Characterized in that the GLP-1R agonis