153587-14-5Relevant articles and documents
Insight into GEBR-32a: Chiral resolution, absolute configuration and enantiopreference in PDE4D inhibition
Brullo, Chiara,Bruno, Olga,Cavalloro, Valeria,Collina, Simona,Donini, Stefano,Parisini, Emilio,Pignataro, Luca,Rapetti, Federica,Rossi, Daniela,Russo, Katia,Semrau, Marta S.,Storici, Paola,Torretta, Archimede,Vasile, Francesca
supporting information, (2020/02/28)
Alzheimer's disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR-32a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR-32a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose-based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H-NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR-32a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains.
Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors
Brullo, Chiara,Massa, Matteo,Villa, Carla,Ricciarelli, Roberta,Rivera, Daniela,Pronzato, Maria Adelaide,Fedele, Ernesto,Barocelli, Elisabetta,Bertoni, Simona,Flammini, Lisa,Bruno, Olga
, p. 3426 - 3435 (2015/08/03)
Abstract A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.
Design, synthesis, and structure - Activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors
Zheng, Shilong,Kaur, Gurpreet,Wang, Huanchen,Li, Minyong,Macnaughtan, Megan,Yang, Xiaochuan,Reid, Suazette,Prestegard, James,Wang, Binghe,Ke, Hengming
experimental part, p. 7673 - 7688 (2009/12/07)
Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC50 values. The most potent compounds have IC50 values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.
