作者: Macina, Justyna ; McCormick, Patricia ; Biddulph, Ross ; Cecconie, Ted ; Macphee, Colin ; Rauch, Martin ; Buxton, Rachel ; Stebbeds, Will ; Gao, Enoch N. ; Wang, Xin ; Brady, Jennifer J. ; Lawler, Meghan ; Bedermann, Aaron ; Lian, Yiqian ; Bingham, Ryan ; Ward, Paris ; Martin, John ; Andrews, Logan ; Pindoria, Rekha ; Marcaurelle, Lisa ; Shen, Yingnian ; Tear, Westley ; Xiao, Shouhua ; Squire, Michael ; Rocque, Warren ; Shewchuk, Lisa M. ; Csakai, Adam ; Yao, Gang ; Grenier-Davies, Melissa C. ; Cooper, Rona ; Rowley, Ann M.

Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.

2012-11-01·Journal of Lipid Research2区 · 生物学

Effects of lipoic acid on lipolysis in 3T3-L1 adipocytes

2区 · 生物学

Article

作者: Pedro L Prieto-Hontoria ; J Alfredo Martinez ; Patricia Pérez-Matute ; Marta Fernández-Galilea ; Maria J Moreno-Aliaga

Lipoic acid (LA) is a naturally occurring compound with beneficial effects on obesity. The aim of this study was to evaluate its effects on lipolysis in 3T3-L1 adipocytes and the mechanisms involved. Our results revealed that LA induced a dose- and time-dependent lipolytic action, which was reversed by pretreatment with the c-Jun N-terminal kinase inhibitor SP600125, the PKA inhibitor H89, and the AMP-activated protein kinase activator AICAR. In contrast, the PI3K/Akt inhibitor LY294002 and the PDE3B antagonist cilostamide enhanced LA-induced lipolysis. LA treatment for 1 h did not modify total protein content of hormone-sensitive lipase (HSL) but significantly increased the phosphorylation of HSL at Ser(563) and at Ser(660), which was reversed by H89. LA treatment also induced a marked increase in PKA-mediated perilipin phosphorylation. LA did not significantly modify the protein levels of adipose triglyceride lipase or its activator comparative gene identification 58 (CGI-58) and inhibitor G(0)/G(1) switch gene 2 (G0S2). Furthermore, LA caused a significant inhibition of adipose-specific phospholipase A2 (AdPLA) protein and mRNA levels in parallel with a decrease in the amount of prostaglandin E(2) released and an increase in cAMP content. Together, these data suggest that the lipolytic actions of LA are mainly mediated by phosphorylation of HSL through cAMP-mediated activation of protein kinase A probably through the inhibition of AdPLA and prostaglandin E(2).

RSC Advances

Design, synthesis, anti-proliferative evaluation, docking, and MD simulation studies of new thieno[2,3-d]pyrimidines targeting VEGFR-2

Article

作者: Eissa, Ibrahim H ; El-Metwally, Souad A ; Ismail, Ahmed ; Husein, Dalal Z ; Hagras, Mohamed ; Elkaeed, Eslam B ; El-Mahdy, Hesham A ; Ibrahim, Ibrahim M ; Taghour, Mohammed S ; Elkady, Hazem ; Metwaly, Ahmed M ; Alsfouk, Bshra A

Design, synthesis, in vitro, and in silico studies of new thieno[2,3-d]pyrimidines as antitumor VEGFR-2 inhibitors with apoptotic activities.

100 项与 PDE3B antagonists(GSK) 相关的药物交易

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