Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of α-alkoxyphenylpropionic acid derived PPAR agonists.

A series of nitrogen heterocycles containing α-ethoxyphenylpropionic acid derivatives were designed as dual PPARα/γ agonist ligands for the treatment of type 2 diabetes (T2D) and its complications. 6-Benzoyl-benzothiazol-2-one was the most tolerant of the tested heterocycles in which incorporation of O-methyl oxime ether and trifluoroethoxy group followed by enantiomeric resolution led to the (S)-stereoisomer 44 b displaying the best in vitro pharmacological profile. Compound 44 b acted as a very potent full PPARγ agonist and a weak partial agonist on the PPARα receptor subtype. Compound 44 b showed high efficacy in an ob/ob mice model with significant decreases in serum triglyceride, glucose and insulin levels but mostly with limited body-weight gain and could be considered as a selective PPARγ modulator (SPPARγM).

New melatonin (MT1/MT2) ligands: design and synthesis of (8,9-dihydro-7H-furo[3,2-f]chromen-1-yl) derivatives.

Herein we describe the synthesis of novel tricyclic analogues issued from the rigidification of the methoxy group of the benzofuranic analogue of melatonin as MT1 and MT2 ligands. Most of the synthesized compounds displayed high binding affinities at MT1 and MT2 receptors subtypes. Compound 6b (MT1, Ki=0.07nM; MT2, Ki=0.08nM) exhibited with the vinyl 6c and allyl 6d the most interesting derivatives of this series. Functional activity of these compounds showed full agonist activity with EC50 in the nanomolar range. Compounds 6a (EC50=0.8nM and Emax=98%) and 6b (EC50=0.2nM and Emax=121%) exhibited good pharmacological profiles.

[Preventing the risk of blood transfusion accidents by identifying gaps in knowledge]. / Prévenr le risque d'accident transfusionnel par le dépistage des connaissances lacunaires.

Working to prevent blood transfusion injury risk, the haemovigilance unit of Tenon hospital in Paris has created a questionnaire to identify staff in need of updating their knowledge. Quick to full in and using the network of partner managers and haemovigilance specialists, this questionnaire enables any latent risks to be identified and an effective training approach to be relaunched.

TGF-ß1 promotes cell barrier function upon maturation of corneal endothelial cells.

Human corneal endothelial cells (HCECs) easily become fibroblastic-like when cultured, rendering them unsuitable for tissue engineering of the cornea. Transforming growth factor ß (TGF-ß) could be a key factor in this phenomenon; however, TGF-ß is also known to maintain the endothelium in a quiescent state in vivo. This work aimed to compare the effects of TGF-ß1 on the phenotype of HCECs during the proliferation and maturation phases. Our results show that addition of TGF-ß1 during the active proliferation phase produced fibroblastic HCECs and loss of the cell junction markers ZO-1 and n-cadherin, independent from the presence of epidermal growth factor (EGF). By contrast, addition of TGF-ß1 in maturation media containing few mitogens led to an endothelial phenotype and functional cell junctions as HCECs developed a high trans-endothelial resistance. Furthermore, addition of AG-1478, an epithelial growth factor receptor inhibitor, enhanced the gain of the endothelial phenotype and cell barrier function. Overall, these results show that TGF-ß1 can be used to promote the formation of a typical leaky endothelial barrier during the maturation phase of cultured HCECs. A two-phase culture of HCECs using distinct proliferation and maturation media could also be key for developing ideal HCEC culture conditions.

Anti-diabetic activity of fused PPARγ-SIRT1 ligands with limited body-weight gain by mimicking calorie restriction and decreasing SGK1 expression.

A series of benzothiazol-2-one containing α-ethoxyphenylpropionic acid derivatives incorporating resveratrol or butein scaffolds were designed as fused full PPARγ agonist ligands and SIRT1-activating compounds for the treatment of type 2 diabetes (T2D) and its complications. Compound 14d displayed the best in vitro pharmacological profile with full PPARγ agonist activity (Emax = 98%, EC50 = 200 nM), SIRT1 enzymatic activation (+128%) and SGK1 expression inhibition (- 57%) which is known to limit side effects as fluid retention and body-weight gain. Compound 14d showed high efficacy in an ob/ob mice model with significant decreases in serum triglyceride, glucose and insulin levels but mostly with limited body-weight gain by mimicking calorie restriction (CR) and inhibiting SGK1 expression.

Understanding the process of corneal endothelial morphological change in vitro.

Corneal endothelial cells often adopt a fibroblastic-like morphology in culture, a process that has been attributed to epithelial- or endothelial-to-mesenchymal transition (EMT or EndMT). Although being extensively studied in other cell types, this transition is less well characterized in the corneal endothelium. Because of their neuroectodermal origin and their in vivo mitotic arrest, corneal endothelial cells represent a particular tissue that deserves more attention. This review article presents the basic principles underlying EMT/EndMT, with emphasis on the current knowledge regarding the corneal endothelium. Furthermore, this review discusses cell culture conditions and major cell signaling pathways that have been identified as EndMT-triggering factors. Finally, it summarizes strategies that have been developed to inhibit EndMT in corneal endothelial cell culture. The review of current studies on corneal and classical EndMT highlights some research avenues to pursue in the future and underscores the need to extend our knowledge of this process in order to optimize usage of these cells in regenerative medicine.

Synthesis of nitroindole derivatives with high affinity and selectivity for melatoninergic binding sites MT(3).

The aim of this study was to synthesize selective ligands for melatoninergic subtype receptors that could elucidate the physiological role of melatonin (N-acetyl-5-methoxytryptamine, 1). So, we first investigated the role of a nitro substituent in the 4-, 6-, or 7-position of the indole heterocycle. Comparatively to melatonin, its analogues that nitrated in the 6- or 7-position (6 and 22) lose MT(3) but retain good MT(1) and MT(2) affinities, whereas the 4-nitro isomer (5) shows very high affinity (nanomolar) and selectivity for the MT(3) binding sites. N-Methylation of the indole nucleus of compound 5 potentiates these effects and affords the most potent and selective MT(3) ligand (17). The 2-iodo derivatives (12 and 10) of compounds 5 and 17 have also been synthesized to evaluate their binding profile with a view to further develop MT(3) selective radioligands.

Effect of oxime ether incorporation in acyl indole derivatives on PPAR subtype selectivity.

Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type 2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20 c and 21 a. Compound 20 c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21 a, less potent as a dual PPARα/γ activator than 20 c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.

Design and synthesis of naphthalenic derivatives as new ligands at the melatonin binding site MT3.

Naphthalenic analogs of MCA-NAT (5-methoxycarbonylamino-N-acetyltryptamine) have been synthesized and evaluated as melatonin receptor ligands. Introduction of a methoxycarbonylamino substituent at the C-7 position of the naphthalenic nucleus yields MT3 selective ligands. This selectivity can be modulated with suitable variations of the C-7 position and the acyl group on the C-1 side chain. We identified new series of compounds with affinity for the MT3 binding site in the nanomolar range, and singled out a selective ligand, (N-[2-(7-methylsulfamoyl-naphth-1-yl)ethyl]acetamide (17), with a Ki of 4.9 nM and selectivity of 1024 and 2040 versus MT1 and MT2 receptors respectively.

Old and new inhibitors of quinone reductase 2.

Quinone reductase 2 is a cytosolic enzyme which catalyses the reduction of quinones, such as menadione and coenzymes Q. Despite a relatively close sequence-based resemblance to NAD(P)H:quinone oxidoreductase 1 (QR1), it has many different features. QR2 is the third melatonin binding site (MT3). It is inhibited in the micromolar range by melatonin, and does not accept conventional phosphorylated nicotinamides as hydride donors. QR2 has a powerful capacity to activate quinones leading to unexpected toxicity situations. In the present paper, we report the characterization of three QR2 modulators: melatonin, resveratrol and S29434. The latter compound inhibits QR2 activity with an IC(50) in the low nanomolar range. The potency of the modulators ranged as follows, from the least to the most potent: melatonin

Novel 1,3-dicarbonyl compounds having 2(3H)-benzazolonic heterocycles as PPARgamma agonists.

A series of 1,3-dicarbonyl compounds having 2(3H)-benzazolonic heterocycles has been synthesized and tested for PPARgamma agonist activity. SAR were developed and revealed that 6-acyl-2(3H)-benzothiazolone derivatives with 1,3-dicarbonyl group were the most potent. IP administration of compound 22 exhibited comparable levels of glucose and triglyceride correction to PO administration of rosiglitazone in the ob/ob mouse studies.