- Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus
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Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy.
- Fujieda, Hiroki,Kogami, Masakazu,Sakairi, Masao,Kato, Noriyasu,Makino, Mitsuhiro,Takahashi, Naoki,Miyazawa, Toshiyuki,Harada, Satoko,Yamashita, Tokuyuki
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- Thiadiazole amide compound and application thereof
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The invention discloses a thiadiazole amide compound and application thereof, and belongs to the field of medicines. The structural general formula of the compound is shown as a formula (I) and is a novel compound with androgen receptor antagonistic activity, wherein one of the key targets is a binding pocket between the androgen receptor ligand binding domain dimer interface. The compound provided by the invention has high activity for antagonizing the transcription of androgen receptor and is at the molecular level. The cell level and the animal level all show good biological activity, and have better safety. , The invention can be applied to the preparation of drugs for treating androgen receptor abnormal expression tumors, including but not limited to prostate cancer, metastatic prostate cancer, castration-resistant prostate cancer, breast cancer and ovarian cancer.
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Paragraph 0072; 0589-0594
(2021/09/29)
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- Novel ASK1 inhibitor and application thereof
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The invention relates to a compound shown as a general formula (I), a pharmacologically acceptable salt, ester or a stereisomer. The invention also relates to a preparation method of the compound, a medicine preparation containing the compound and a medic
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Paragraph 0176; 0189-0191
(2019/10/15)
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- HETEROCYCLIC COMPOUNDS AS INHIBITORS OF RAS AND METHODS OF USE THEREOF
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Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, B, R", Q, W, X, Y, Z, n1, n2and '--" are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also disclosed.
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Page/Page column 132
(2018/04/21)
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- COMPOUNDS TARGETING PROTEINS, COMPOSITIONS, METHODS, AND USES THEREOF
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The present invention provides compounds that modulate protein function, to restore protein homeostasis, including cytokine, CK1α, GSPT1, aiolos, and/or ikaros activity, and cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions, including in combination with other cytokine and inflammatory mediators, are provided. Methods of treatment, amelioration, or prevention of diseases, disorders, or conditions associated with a protein, such as diseases, disorders, and conditions associated with cytokines, including inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer's disease, and cancer, are provided.
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Paragraph 0406
(2018/07/04)
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- Design, synthesis, and structure-activity relationship studies of novel thienopyrrolidone derivatives with strong antifungal activity against Aspergillus fumigates
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In order to further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (I), two series of novel azoles featuring thieno[2,3-c]pyrrolidone and thieno[3,2-c]pyrrolidone nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SARs of antifungal triazoles. Most of target compounds exhibited excellent activity against Candida and Cryptococcus spp., with MIC values in the range of 0.0625 μg/ml to 0.0156 μg/ml. The thieno[3,2-c]pyrrolidone unit was more suited for improving activity against Aspergillus spp. The most potent compound, 18a, was selected for further development due to its significant in vitro activity against Aspergillus spp. (MIC Combining double low line 0.25 μg/ml), as well as its high metabolic stability in human liver microsomes.
- Cao, Xufeng,Xu, Yuanyuan,Cao, Yongbing,Wang, Ruilian,Zhou, Ran,Chu, Wenjing,Yang, Yushe
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p. 471 - 476
(2015/09/01)
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- NOVEL THIOPHENECARBOXAMIDE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
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The object of the present invention is to provide a compound having a glucokinase-activating effect. A pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient: wherein X means a nitrogen atom or CR6, wherein R6 means a hydrogen atom or a halogen atom; R1 means a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylthio group; R2 means a hydrogen atom or a fluorine atom; R3 means a hydrogen atom or a C1-C6 alkyl group; and one of R4 and R5 means a hydrogen atom or a C1-C6 alkyl group, and the other means a C1-C6 alkylenecarboxylic acid, a C1-C6 alkylsulfonyl group, a C1-C6 alkylcarbonyl group, or CONH2.
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- Discovery and hit-to-lead optimization of novel allosteric glucokinase activators
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We report on a hit generation and hit-to-lead program of a novel class of glucokinase activators (GKAs). Hit compounds, activators at low glucose concentration only were identified by vHTS. Scaffold modification reliably afforded activators also at high s
- Lang, Martin,Seifert, Markus H.-J.,Wolf, Kristina K.,Aschenbrenner, Andrea,Baumgartner, Roland,Wieber, Tanja,Trentinaglia, Viola,Blisse, Marcus,Tajima, Nobumitsu,Yamashita, Tokuyuki,Vitt, Daniel,Noda, Hitoshi
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p. 5417 - 5422
(2011/10/12)
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