Novel GPR119 agonist HD0471042 attenuated type 2 diabetes mellitus

Ha, Tae-Young,Kim, Young-Seok,Kim, Chun Hwa,Choi, Hyo-Sun,Yang, Jin,Park, Soo Hyun,Kim, Dae Hoon,Rhee, Jae-Keol 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.5

In type 2 diabetes mellitus (T2DM) patients, the gradual loss of pancreatic ${\beta}$-cell function is a characteristic feature of disease progression that is associated with sustained hyperglycemia. Recently, G protein-coupled receptor 119 (GPR119) has been identified as a promising anti-diabetic therapeutic target. It is predominantly expressed in pancreatic ${\beta}$-cells, directly promotes glucose stimulated insulin secretion and indirectly increases glucagon-like peptide 1 (GLP-1) levels reducing appetite and food intake. Activation of GPR119 leads to insulin release in ${\beta}$-cells by increasing intracellular cAMP. Here, we identified a novel structural class of small-molecule GPR119 agonists, HD0471042, consisting of substituted a 3-isopropyl-1,2,4-oxadiazol-piperidine derivative with promising potential for the treatment of T2DM. The GPR119 agonist, HD0471042 increased intracellular cAMP levels in stably human GPR119 expressing CHO cell lines and HIT-T15 cell lines, hamster ${\beta}$-cell line expressing endogenously GPR119. HD0471042, significantly elevated insulin release in INS-1 cells of rat pancreatic ${\beta}$-cell line. In in vivo experiments, a single dose of HD0471042 improved glucose tolerance. Insulin and GLP-1 level were increased in a dose-dependent manner. Treatment with HD0471042 for 6 weeks in diet induced obesity mice and for 4 weeks in ob/ob and db/db mice improved glycemic control and also reduced weight gain in a dose-dependent manner. These data demonstrate that the novel GPR119 agonist, HD0471042, not only effectively controlled glucose levels, but also had an anti-obesity effect, a feature observed with GLP-1. We therefore suggest that HD0471042 represents a new type of anti-diabetes agent with anti-obesity potential for the effective treatment of type 2 diabetes.

Novel GPR119 agonist HD0471042 attenuated type 2 diabetes mellitus

하태영,김영석,김춘화,최효선,양진,박수현,김대훈,이재걸 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.5

In type 2 diabetes mellitus (T2DM) patients, thegradual loss of pancreatic b-cell function is a characteristicfeature of disease progression that is associated with sustainedhyperglycemia. Recently, G protein-coupled receptor119 (GPR119) has been identified as a promising anti-diabetictherapeutic target. It is predominantly expressed inpancreatic b-cells, directly promotes glucose stimulatedinsulin secretion and indirectly increases glucagon-like peptide1 (GLP-1) levels reducing appetite and food intake. Activation of GPR119 leads to insulin release in b-cells byincreasing intracellular cAMP. Here, we identified a novelstructural class of small-molecule GPR119 agonists,HD0471042, consisting of substituted a 3-isopropyl-1,2,4-oxadiazol-piperidine derivative with promising potential forthe treatment of T2DM. The GPR119 agonist, HD0471042increased intracellular cAMP levels in stably human GPR119 expressing CHO cell lines and HIT-T15 cell lines, hamster bcellline expressing endogenously GPR119. HD0471042,significantly elevated insulin release in INS-1 cells of ratpancreatic b-cell line. In in vivo experiments, a single dose ofHD0471042 improved glucose tolerance. Insulin and GLP-1level were increased in a dose-dependent manner. Treatmentwith HD0471042 for 6 weeks in diet induced obesity miceand for 4 weeks in ob/ob and db/db mice improved glycemiccontrol and also reduced weight gain in a dose-dependentmanner. These data demonstrate that the novel GPR119agonist, HD0471042, not only effectively controlled glucoselevels, but also had an anti-obesity effect, a feature observedwith GLP-1. We therefore suggest that HD0471042 representsa new type of anti-diabetes agent with anti-obesitypotential for the effective treatment of type 2 diabetes.

Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists

Kim, Hyojin,Cho, Suk Joon,Yoo, Minjin,Kang, Seung Kyu,Kim, Kwang Rok,Lee, Hwan Hee,Song, Jin Sook,Rhee, Sang Dal,Jung, Won Hoon,Ahn, Jin Hee,Jung, Jae-Kyung,Jung, Kwan-Young Elsevier 2017 Bioorganic & medicinal chemistry letters Vol.27 No.23

<P><B>Abstract</B></P> <P>A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound <B>27</B> and <B>32d</B> showed good <I>in vitro</I> activity with an EC<SUB>50</SUB> value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound <B>27</B> &<B>32d</B> did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

HD047703, a New Promising Anti-Diabetic Drug Candidate: In Vivo Preclinical Studies

( So Ra Kim ),( Dae Hoon Kim ),( Young Seok Kim ),( Tae Young Ha ),( Jin Yang ),( Soo Hyun Park ),( Kwang Won Jeong ),( Jae Keol Rhee ) 한국응용약물학회 2014 Biomolecules & Therapeutics(구 응용약물학회지) Vol.22 No.5

G-protein coupled receptor 119 (GPR119) has emerged as a novel target for the treatment of type 2 diabetes mellitus. GPR119 is involved in glucose-stimulated insulin secretion (GSIS) from the pancreatic b-cells and intestinal cells. In this study, we identified a novel small-molecule GPR119 agonist, HD047703, which raises intracellular cAMP concentrations in pancreatic β-cells and can be expected to potentiate glucose-stimulated insulin secretion from human GPR119 receptor stably expressing cells (CHO cells). We evaluated the acute efficacy of HD047703 by the oral glucose tolerance test (OGTT) in normal C57BL/6J mice. Then, chronic administrations of HD047703 were performed to determine its efficacy in various diabetic rodent models. Single administration of HD047703 caused improved glycemic control during OGTT in a dose-dependent manner in normal mice, and the plasma GLP-1 level was also increased. With respect to chronic efficacy, we observed a decline in blood glucose levels in db/db, ob/ob and DIO mice. These results suggest that HD047703 may be a potentially promising anti-diabetic agent.

Synthesis and biological evaluation of pyrimidine derivatives with diverse azabicyclic ether/amine as novel GPR119 agonist

Yang, Zunhua,Fang, Yuanying,Park, Haeil Pergamon Press 2017 Bioorganic & medicinal chemistry letters Vol.27 No.11

<P><B>Abstract</B></P> <P>A class of novel pyrimidine derivatives bearing diverse conformationally restricted azabicyclic ether/amine were designed, synthesized and evaluated for their GPR119 agonist activities against type 2 diabetes. Most compounds exhibited superior hEC<SUB>50</SUB> values to endogenous lipid oleoylethanolamide (OEA). Analogs with 2-fluoro substitution in the aryl ring showed more potent GPR119 activation than those without fluorine. Especially compound <B>27m</B> synthesized from <I>endo</I>-azabicyclic alcohol was observed to have the best EC<SUB>50</SUB> value (1.2nM) and quite good agonistic activity (112.2% max) as a full agonist.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

YH18968, a Novel 1,2,4-Triazolone G-Protein Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes Mellitus

한태동,이병문,박유회,이동훈,최현호,이태훈,김학원 한국응용약물학회 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.2

G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.

YH18968, a Novel 1,2,4-Triazolone G-Protein Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes Mellitus

( Taedong Han ),( Byoung Moon Lee ),( Yoo Hoi Park ),( Dong Hoon Lee ),( Hyun Ho Choi ),( Taehoon Lee ),( Hakwon Kim ) 한국응용약물학회 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.2

G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.

YH18968, a Novel 1,2,4-Triazolone G-Protein Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes Mellitus

Han, Taedong,Lee, Byoung Moon,Park, Yoo Hoi,Lee, Dong Hoon,Choi, Hyun Ho,Lee, Taehoon,Kim, Hakwon The Korean Society of Applied Pharmacology 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.2

G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.

A Novel Small Molecule GPR119 Agonist HD0470544 Improved Glycemic Control in Type 2 Diabetic Animal Models

김춘화,김영석,김소라,하태영,양고은,강승준,이선희,양진,김대훈,이재걸 한국실험동물학회 2014 한국실험동물학회 학술발표대회 논문집 Vol.2014 No.2

피리다진계 항당뇨 화합물의 합성 및 평가

보두이비엣(Duy-Viet Vo),박해일(Haeil Park) 대한약학회 2021 약학회지 Vol.65 No.4

3,6-Disubstituted pyridazine analogs (2a and 2b) were synthesized from commercially available 3,6- dichloropyridazine in two steps. The synthesized compounds were evaluated for their GPR119 agonistic activity. Both compounds exhibited much stronger EC50 values than that of oleylethanolamide (OEA) and were proved to be partial agonists. These results indicate that the pyridazine ring can be used as a potential heterocycle scaffold for GPR119 agonists.