• Non ci sono risultati.

Discovery and optimization of benzoylpiperidine derivatives as new reversible, potent and selective MAGL inhibitors

N/A
N/A
Protected

Academic year: 2021

Condividi "Discovery and optimization of benzoylpiperidine derivatives as new reversible, potent and selective MAGL inhibitors"

Copied!
1
0
0

Testo completo

(1)

Discovery and optimization of benzoylpiperidine derivatives

as new reversible, potent and selective MAGL inhibitors

Carlotta Granchi,

a

Giulia Bononi,

a

Flavio Rizzolio,

b

Andrea Chicca,

c

Tiziano

Tuccinardi,

a

and Filippo Minutolo

a

a Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy. b Department of Molecular Sciences and Nanosystems, Ca' Foscari University, Via Torino 155,

30172 Mestre (Venezia), Italy.

c Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern,

Bühlstrasse 28, 3012 Bern, Switzerland. E-mail: carlotta.granchi@unipi.it

The serine hydrolase monoacylglycerol lipase (MAGL) is the main responsible of the degradation of 2-arachidonoylglycerol, an endocannabinoid implicated in several physiological processes. Moreover, MAGL is involved in the formation of pro-tumorigenic signaling molecules. MAGL inhibition is considered a valid therapeutic approach to treat several pathological conditions, including several types of cancer.[1] So far, only a limited number of MAGL inhibitors have been discovered and most of them are characterized by an irreversible mechanism of action, determining the occurrence of undesired effects. In this study we identified a reversible MAGL inhibitor by a structure-based virtual screening analysis. With the aim of identifying more potent and selective MAGL inhibitors, chemical modifications were introduced to the original compound to improve both potency and selectivity.[2] The structural optimization led to the obtainment of nanomolar inhibitors (Figure 1), which are selective over other hydrolases and cannabinoid receptors. These new inhibitors exert an appreciable antiproliferative activity in cancer cells and are able to inhibit MAGL in in vivo assays.

Figure 1: Putative binding disposition of one of the best inhibitors in MAGL active site.

[1] Mulvihill MM, Nomura DK, Life Sci. 2013; 92(8-9):492-497.

[2] Granchi C, Rizzolio F, Palazzolo S, Carmignani S, Macchia M, Saccomanni G, Manera C, Martinelli A, Minutolo F, Tuccinardi T, J Med Chem. 2016; 59(22):10299-10314.

Riferimenti

Documenti correlati

In altri termini il cosiddetto spirito della frontiera trova terreno fertile in questa particolare forma di puritanesimo, almeno sin quando c’è spazio fisico a

(d) Western blot analysis of the h.MPV17 protein: the amount detected in isolated liver mitochondria from three AAV-treated Mpv17 −/− mice is higher than that detected in Mpv17 -/+

Supporting Information. The supporting information file includes a) Figure S1 showing the atomistic details of the Au NP model; b) Figure S2 and S3 with details concerning our

#Day4 Da dove vengono le buone idee? Per essere innovativi bisogna per forza essere artisti? Ne abbiamo parlato con il Prof. Andrea Bonaccorsi, ordinario di Ingegneria Gestionale

In this contribution we summarize results on the search for vari- able stars and the study of the resolved stellar populations in four dwarf spheroidal satellites of the

Placing our results in this context, the reverberation radii derived from the 3.6 and 4.5 μm light curves are consistent with the variable emission at these wavelengths arising in

due to model degeneracy and photo-z uncertainty All the stellar mass estimates that we are considering and comparing in the present work are computed by as- suming the photometric

Stellar models, globular and open clusters, satellite dwarfs: all are tracers of the chemical and dynamical evolution of the MW and LG