Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
摘要:
A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
摘要:
A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
Novel polyimide compositions and novel acid dianhydrides to be used therein
申请人:KANEKA CORPORATION
公开号:US20020055610A1
公开(公告)日:2002-05-09
Novel polyimides substituted by a substituent having an alkyl or fluoroalkyl group and having reduced water absorption; a process for producing these novel polyimides; and novel acid dianhydrides to be used in the production thereof.
A polyimide containing a structure represented by the following general formula (I):
1
wherein
X
1
represents a tetravalent organic group having a substituent —R
1
AR
2
(wherein A represents a divalent linkage group; R
1
represents a single bond or a C
1-3
alkylene group; and R
2
represents a C
1-25
alkyl group or a fluoroalkyl group); and
Y represents a divalent organic group.
[EN] CURABLE RESIN COMPOSITION, CURED OBJECT, LAYERED PRODUCT, METHOD FOR PRODUCING CURED OBJECT, SEMICONDUCTOR DEVICE, AND PHOTOBASE GENERATOR<br/>[FR] COMPOSITION DE RÉSINE DURCISSABLE, OBJET DURCI AINSI QUE PROCÉDÉ DE FABRICATION DE CELUI-CI, STRATIFIÉ, DISPOSITIF À SEMI-CONDUCTEURS, ET GÉNÉRATEUR DE PHOTOBASE<br/>[JA] 硬化性樹脂組成物、硬化物、積層体、硬化物の製造方法、及び、半導体デバイス、並びに、光塩基発生剤
Melt-fusible polyimides based on pyromellitic dianhydride and at least one defined aromatic diamine are useful in making low-void composites and thermoplastic tapes, which can be fabricated into articles such as, for example, aircraft and autobody panels, printed circuit boards, etc. Some of these polyimides are melt-processible and can be fabricated by conventional procedures such as extrusion and injection molding.
Light-absorbing resins for display device, display devices using the resin and method of manufacturing the same
申请人:KABUSHIKI KAISHA TOSHIBA
公开号:EP0231953A2
公开(公告)日:1987-08-12
For the display apparatus that uses an electro-optic modulating material such as liquid crystal, use is made of a thin film transistor which possesses a good response, as the driving element. In this transistor, there is provided a light-absorbing resin layer that is formed by a polyimide and a light absorber to prevent malfunctions due to light. A method of manufacturing the display apparatus is disclosed.
Novel polyamide-polyamide and polybenzoxazole-polyamide polymers
申请人:HOECHST CELANESE CORPORATION
公开号:EP0387061A2
公开(公告)日:1990-09-12
The present invention provides polyamide-polyamide and polybenzoxazole-polyamide polymers derived therefrom with improved processing and film characteristics having incorporated into the polymeric backbone the polymeric condensation residuum of novel aromatic diamino compounds having the formula:
wherein A is selected from the group consisting of S02, 0, S, CO, C1 to C6 alkyl, perfluoroalkyl or perfluoroarylalkyl having from 1 to 10 carbon atoms and a carbon-carbon double bond directly linking the two aromatic groups and R is selected from the group consisting of hydrogen, hydroxy and C1 to C4 alkoxy.
The polyamide-polyamide polymers of this invention are prepared by reacting compounds of the above formula, alone or admixed with other aromatic diamines, with one or more aromatic or aliphatic dicarboxylic acids or amide-forming derivatives thereof. Polybenzoxazole-polyamide derivatives of such polyamide-polyamide polymers are prepared utilizing compounds of the above formula wherein R is hydroxy or C, to C4 alkoxy, and by subjecting the resulting alkoxy or hydroxy-substituted polyamide-polyamide to a dehydrating and cyclizing reaction to form the oxazole linkage which gives rise to polybenzoxazole-polyamide polymer.