- Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27
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GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called “Super-Conserved Receptors Expressed in the Brain” (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic β-cell insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC50 6.34, Emax 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC50 6.85, Emax 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC50 6.04, Emax 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC50 5.99, Emax 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.
- Blavier, Jeremy,Charles, Ma?lle,Hanson, Julien,Kronenberger, Thales,Laschet, Céline,Müller, Christa E.,Pillaiyar, Thanigaimalai,Rosato, Francesca,Wozniak, Monika
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- 6-OXO-1,6-DIHYDROPYRIDAZINE DERIVATIVE, PREPARATION METHOD THEREFOR AND MEDICAL USE THEREOF
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A 6-oxo-1,6-dihydropyridazine derivative, a preparation method therefor and medical use thereof, in particular, a 6-oxo-1,6-dihydropyridazine derivative represented by general formula (I), a preparation method therefor, and a pharmaceutical composition containing the derivative, and use thereof as a NaV inhibitor and use thereof in the preparation of a drug for the treatment and/or prevention of pain and pain-related diseases. Each substituent in general formula (I) is the same as defined in the description.
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Paragraph 0145-0146; 0177-0178
(2021/11/14)
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- AMIDE COMPOUND OR SALT THEREOF, AND BACTERICIDE FOR AGRICULTURAL AND HORTICULTURAL USE CONTAINING THE COMPOUND, AND METHOD OF USING THE SAME
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PROBLEM TO BE SOLVED: To provide a novel bactericide for agricultural and horticultural use having excellent spreadability and diffusibility. SOLUTION: The present invention provides an amide compound produced by, for example, the following reaction formula, and a salt thereof. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0128; 0129-0130
(2020/07/16)
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- Discovery of [1,2,4]triazolo[4,3-a]pyridines as potent Smoothened inhibitors targeting the Hedgehog pathway with improved antitumor activity in vivo
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Triple-negative breast cancer (TNBC), a subset of breast cancers, have poorer survival than other breast cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it's necessary to develop novel Smo inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against cancer cell lines in vitro, especially triple-negative breast cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Gli1) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists.
- Chen, Mian,Lv, Lin,Quan, Dongling,Schmitz, John C.,Tian, Nannan,Tian, Yuanxin,Wei, Ning,Wu, Huanxian,Wu, Shaoyu,Xie, Ying,Xu, Yimei,Yang, Danni,Yang, Zichao,Zhang, Huiwu,Zhang, Jiajie,Zhang, Tingting,Zhou, Lei
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- PROCESS FOR MAKING PYRIDONE AMIDES AND PRODRUGS THEREOF USEFUL AS MODULATORS OF SODIUM CHANNELS
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The present application is directed to a process of preparing compounds of formula I, and intermediates thereof as well as pharmaceutically acceptable salts, wherein R2, R3, R5, R7 and X are defined herein. The
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Paragraph 00256
(2020/10/19)
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- Site-Selective Silylation of Aliphatic C-H Bonds Mediated by [1,5]-Hydrogen Transfer: Synthesis of α-Sila Benzamides
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The first example of site-selective silylation of C(sp3)-H bonds mediated by a [1,5]-hydrogen transfer is reported. This reaction occurs selectively at the α-position of benzamides with a combination of tert-butylmagnesium chloride and a catalytic amount of 4,4′-di-tert-butylbipyridine (dtbpy) ligand and provides a facile route for the creation of biologically interesting α-sila benzamides. Late-stage functionalization of the incorporated silyl moieties facilitates the synthesis of N-formyl, cis-enamine, β-hydroxyl, amino, and pyrrole-containing derivatives.
- Liu, Pei,Tang, Jinghua,Zeng, Xiaoming
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supporting information
p. 5536 - 5539
(2016/11/17)
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- The discovery and initial optimisation of pyrrole-2-carboxamides as inhibitors of p38α MAP kinase
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A novel pyrrole-2-carboxamide series of p38α inhibitors, discovered through the application of virtual screening, is presented. Following evaluation of activity, selectivity and developability properties of commercially available analogues, a synthesis program enabled rapid assessment of the series' suitability for further lead optimisation studies.
- Down, Kenneth,Bamborough, Paul,Alder, Catherine,Campbell, Amanda,Christopher, John A.,Gerelle, Maria,Ludbrook, Steve,Mallett, Dave,Mellor, Geoff,Miller, David D.,Pearson, Rosannah,Ray, Keith,Solanke, Yemisi,Somers, Don
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scheme or table
p. 3936 - 3940
(2010/08/19)
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- A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors
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Distinct from previously reported urea and amide inhibitors of soluble epoxide hydrolase (sEH), a novel class of inhibitors were rationally designed based on the X-ray structure of this enzyme and known amide inhibitors. The structure-activity relationshi
- Shen, Hong C.,Ding, Fa-Xiang,Deng, Qiaolin,Xu, Suoyu,Tong, Xinchun,Zhang, Xiaoping,Chen, Yuli,Zhou, Gaochao,Pai, Lee-Yuh,Alonso-Galicia, Magdalena,Roy, Sophie,Zhang, Bei,Tata, James R.,Berger, Joel P.,Colletti, Steven L.
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experimental part
p. 5716 - 5721
(2010/04/30)
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- Amino acid derivatives
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Described herein are compounds having the general formula: wherein: Ar1 and Ar2 are independently selected aryl groups, optionally substituted with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkanoyl, aralkyl, aralkyloxy
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