123724-16-3Relevant articles and documents
Structural Basis for Developing Multitarget Compounds Acting on Cysteinyl Leukotriene Receptor 1 and G-Protein-Coupled Bile Acid Receptor 1
Fiorillo, Bianca,Sepe, Valentina,Conflitti, Paolo,Roselli, Rosalinda,Biagioli, Michele,Marchianò, Silvia,De Luca, Pasquale,Baronissi, Giuliana,Rapacciuolo, Pasquale,Cassiano, Chiara,Catalanotti, Bruno,Zampella, Angela,Limongelli, Vittorio,Fiorucci, Stefano
, p. 16512 - 16529 (2021/11/24)
G-protein-coupled receptors (GPCRs) are the molecular target of 40% of marketed drugs and the most investigated structures to develop novel therapeutics. Different members of the GPCRs superfamily can modulate the same cellular process acting on diverse pathways, thus representing an attractive opportunity to achieve multitarget drugs with synergic pharmacological effects. Here, we present a series of compounds with dual activity toward cysteinyl leukotriene receptor 1 (CysLT1R) and G-protein-coupled bile acid receptor 1 (GPBAR1). They are derivatives of REV5901-the first reported dual compound-with therapeutic potential in the treatment of colitis and other inflammatory processes. We report the binding mode of the most active compounds in the two GPCRs, revealing unprecedented structural basis for future drug design studies, including the presence of a polar group opportunely spaced from an aromatic ring in the ligand to interact with Arg792.60 of CysLT1R and achieve dual activity.
Radiosynthesis and in vivo evaluation of [11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain
Tu, Zhude,Fan, Jinda,Li, Shihong,Jones, Lynne A.,Cui, Jinquan,Padakanti, Prashanth K.,Xu, Jinbin,Zeng, Dexing,Shoghi, Kooresh I.,Perlmutter, Joel S.,MacH, Robert H.
, p. 1666 - 1673 (2011/04/16)
2-((4-(1-[11C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy) methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC50 = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [11C]CH3I, ～45% yield, >92% radiochemical purity, >370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [11C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [11C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood-brain-barrier may limit the clinical utility of [11C]MP-10 as a PDE10A PET tracer.
Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3- yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia
Verhoest, Patrick R.,Chapin, Douglas S.,Corman, Michael,Fonseca, Kari,Harms, John F.,Hou, Xinjun,Marr, Eric S.,Menniti, Frank S.,Nelson, Frederick,O'Connor, Rebecca,Pandit, Jayvardhan,Proulx-LaFrance, Caroline,Schmidt, Anne W.,Schmidt, Christopher J.,Suiciak, Judith A.,Liras, Spiros
experimental part, p. 5188 - 5196 (2010/03/01)
By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.
