137426-86-9Relevant 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.
supporting information; experimental part, 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.
BICYCLIC HETEROARYL COMPOUNDS AS PDE10 INHIBITORS
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Page/Page column 20, (2009/07/18)
The invention pertains to tricyclic heteraaryi compounds that serve as effective phosphodiesterase (PDE) inhibitors. The invention also relates to compounds which are selective inhibitors of PDE 10. The invention further relates to pharmaceutical compositions comprising such compounds; and the use of such compounds in methods for treating certain central nervous system (CNS) or other disorders. The invention relates also to methods for treating neurodegenerative and psychiatric disorders, for example psychosis and disorders comprising deficient cognition as a symptom.
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.
Heteroaromatic quinoline compounds
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Page/Page column 23, (2008/06/13)
The invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. In particular, the invention relates to said compounds which are selective inhibitors of PDE10. The invention also relates to intermediates for preparation of said compounds; pharmaceutical compositions comprising said compounds; and the use of said compounds in a method for treating certain central nervous system (CNS) or other disorders.
PHOSPHODIESTERASE 10 INHIBITION AS TREATMENT FOR OBESITY-RELATED AND METABOLIC SYNDROME-RELATED CONDITIONS
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Page/Page column 21, (2008/06/13)
The present invention provides methods to decrease body weight and/or body fat in animals, e.g., in the treatment of overweight or obese patients (e.g., humans or companion animals), or as a means to produce leaner meat in food stock animals (e.g., cattle, chickens, pigs), methods to treat non-insulin dependent diabetes (NIDDM), metabolic syndrome, or glucose intolerance, in patients in need thereof by administering a PDE10 inhibitor (alone or in combination with another therapeutic agent), kits for the above-identified therapeutic uses, and methods of identifying PDE10 inhibitors for the above-described therapeutic uses.
CARBAMIC ACID COMPOUNDS COMPRISING A BICYCLIC HETEROARYL GROUP AS HDAC INHIBITORS
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Page 107, (2010/02/08)
This invention pertains to certain carbamic acid compounds of the following formula, which inhibit HDAC (histone deacetylase) activity wherein: A is independently an unsubstituted or substituted bicyclic C9-10heteroaryl group (e.g., quinolinyl; quinoxalinyl; benzoxazolyl; benzothiazolyl); Q is an acid leader group, and is independently an unsubstituted or substituted, saturated or unsaturated C1 7alkylene group having a backbone length of 4 or less; with the proviso that if A is unsubstituted benzothiazol-2-yl, then Q is an unsaturated group; and with the proviso that if A is unsubstituted quinolin-6-yl, then Q is unsubstituted at the α-position; and with the proviso that A is not benzimidazol-2-yl; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both invitro and in vivo, to inhibit HDAC, and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc.
CYANOMETHYLPYRIDINE DERIVATIVES
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, (2008/06/13)
The present invention relates to new cyanomethylpyridine dervatives of formula I wherein Y represents N or CH;R1 represents hydrogen, fluoro, chloro, difluoro or dichloro; R2 represents hydrogen or C1-4alkyl;n is 0 or 1; p is 0 or 1; A represents a covalent bond or a group of formula -CONHC-H(Ar)-, -NHCH(Ar)-, -S02NHCH(Ar)-,NHCONHCH(Ar) or OCONHCH(Ar),and when p is 1,A can also represent CH(Ar)NH; and AT represents phenyl or phenyl substituted with halogen,C M alkyl, C1-4 alkoxy or trifluoromethyl. These compounds are PAF antagonist and/or 5-lipoxygenase inhibitors.
