- Multitarget Approach for the Treatment of Alzheimer's Disease: Inhibition of Phosphodiesterase 9 (PDE9) and Histone Deacetylases (HDACs) Covering Diverse Selectivity Profiles
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Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochemical screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).
- Rabal, Obdulia,Sánchez-Arias, Juan A.,Cuadrado-Tejedor, Mar,De Miguel, Irene,Pérez-González, Marta,García-Barroso, Carolina,Ugarte, Ana,Estella-Hermoso De Mendoza, Ander,Sáez, Elena,Espelosin, Maria,Ursua, Susana,Tan, Haizhong,Wu, Wei,Xu, Musheng,Pineda-Lucena, Antonio,Garcia-Osta, Ana,Oyarzabal, Julen
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p. 4076 - 4101
(2019/10/14)
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- Design, Synthesis, and Biological Evaluation of Dual-Target Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 9A (PDE9A) for the Treatment of Alzheimer's Disease
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A series of dual-target AChE/PDE9A inhibitor compounds were designed, synthesized, and evaluated as anti-Alzheimer's Disease (AD) agents. Among these target compounds, 11a (AChE: IC50 = 0.048 μM; PDE9A: IC50 = 0.530 μM) and 11b (AChE: IC50 = 0.223 μM; PDE9A: IC50 = 0.285 μM) exhibited excellent and balanced dual-target AChE/PDE9A inhibitory activities. Meanwhile, those two compounds possess good blood-brain barrier (BBB) penetrability and low neurotoxicity. Especially, 11a and 11b could ameliorate learning deficits induced by scopolamine (Scop). Moreover, 11a could also improve cognitive and spatial memory in Aβ25-35-induced cognitive deficit mice in the Morris water-maze test. In summary, our research developed a series of potential dual-target AChE/PDE9A inhibitors, and the data indicated that 11a was a promising candidate drug for the treatment of AD.
- Hu, Jinhui,Huang, Ya-Dan,Pan, Tingting,Zhang, Tianhua,Su, Tao,Li, Xingshu,Luo, Hai-Bin,Huang, Ling
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p. 537 - 551
(2018/10/24)
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- Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer’s disease
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Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer’s disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, couplin
- Zhang, Chen,Zhou, Qian,Wu, Xu-Nian,Huang, Yat-sen,Zhou, Jie,Lai, Zengwei,Wu, Yinuo,Luo, Hai-Bin
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p. 260 - 270
(2017/12/28)
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- N-substituted pyrazolo [3, 4-d] pyrimidone compound and preparation method and application thereof
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The invention discloses a preparation method and application of a N-substituted pyrazolo [3, 4-d] pyrimidone compound. The compound has the structure shown in formula 1, wherein R is a cyclic or non cyclic fatty alkyl group, a heterocyclic group, an acyl-
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Paragraph 0023; 0024
(2017/08/24)
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- Discovery of Novel Pyrazolopyrimidinone Derivatives as Phosphodiesterase 9A Inhibitors Capable of Inhibiting Butyrylcholinesterase for Treatment of Alzheimer's Disease
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Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 μM; 6f, 0.97 μM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.
- Yu, Yan-Fa,Huang, Ya-Dan,Zhang, Chen,Wu, Xu-Nian,Zhou, Qian,Wu, Deyan,Wu, Yinuo,Luo, Hai-Bin
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p. 2522 - 2534
(2017/11/21)
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- NOVEL COMPOUNDS FOR USE IN COGNITION IMPROVEMENT
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Novel compounds for use in cognition improvement It relates to certain compounds having a polycyclic structure and a -(C=O)NRaRb moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases.
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Page/Page column 78
(2016/04/19)
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- PYRAZOLO[3,4-D]PYRIMIDIN-4(5H)-ONE DERIVATIVES AS PDE9 INHIBITORS
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A compound of the general formula (I) wherein R1 is selected from the group consisting of phenyl unsubstituted or substituted with 1 to 3 substituents selected from F, Cl, Br, I, CN, -O-C1-C3-alkyl, fluorinated -O-C1-C3-alkyl, -(CH2)mOH and 5-membered heterocyclic group with 1 or 2 heteroatoms selected from N, O and S; and 6- or 10-membered heteroaryl with 1 to 3 heteroatoms selected from O, N and S; R2 and R3 independently of each other represent H atom or straight or branched C1-C3 alkyl; R4 is selected from the group consisting of 4- to 6- membered cycloalkyl, wherein one of carbon atoms can be replaced by O atom, and which is unsubstituted or substituted with one or two halogen atoms,and straight or branched C1-C4 alkyl; Q represents a bond or C1-C3-alkylene, which can be optionally substituted by one to three C1-C3-alkyls; X is selected from the group consisting of O, NR5, and S(O)p; R5 represents H atom or C1-C3alkyl; m is 1, 2 or 3; p is 0, 1 or 2; and salts thereof, for use as a medicament, in particular for treating cognitive function disorders and neurodegenerative diseases.
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Page/Page column 19; 20
(2014/02/16)
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- NOVEL COMPOUNDS AS DUAL INHIBITORS OF PHOSPHODIESTERASES AND HISTONE DEACETYLASES
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It relates to certain compounds having a polycyclic structure and a hydroxamic acid moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to a process for their preparation, as well as to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases. wherein B1 is a radical selected from the group consisting of formula (A"), formula (B"), formula (C"), and formula (D"):
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Page/Page column 151; 152
(2014/09/16)
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- Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors
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Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimers disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.
- Claffey, Michelle M.,Helal, Christopher J.,Verhoest, Patrick R.,Kang, Zhijun,Fors, Kristina S.,Jung, Stanley,Zhong, Jiaying,Bundesmann, Mark W.,Hou, Xinjun,Lui, Shenping,Kleiman, Robin J.,Vanase-Frawley, Michelle,Schmidt, Anne W.,Menniti, Frank,Schmidt, Christopher J.,Hoffman, William E.,Hajos, Mihaly,McDowell, Laura,Oconnor, Rebecca E.,MacDougall-Murphy, Mary,Fonseca, Kari R.,Becker, Stacey L.,Nelson, Frederick R.,Liras, Spiros
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p. 9055 - 9068
(2013/01/15)
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- AMINO-HETEROCYCLIC COMPOUNDS
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The invention provides PDE9-inhibiting compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, A, and n are as defined herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in treating neurodegenerative and cognitive disorders, such as Alzheimer's disease and schizophrenia, are also provided.
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Page/Page column 19-20
(2010/08/07)
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- Identification of a brain penetrant PDE9A inhibitor utilizing prospective design and chemical enablement as a rapid lead optimization strategy
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By use of chemical enablement and prospective design, a novel series of selective, brain penetrant PDE9A inhibitors have been identified that are capable of producing in vivo elevations of brain cGMP.
- Verhoest, Patrick R.,Proulx-Lafrance, Caroline,Corman, Michael,Chenard, Lois,Helal, Christopher J.,Hou, Xinjun,Kleiman, Robin,Liu, Shenping,Marr, Eric,Menniti, Frank S.,Schmidt, Christopher J.,Vanase-Frawley, Michelle,Schmidt, Anne W.,Williams, Robert D.,Nelson, Frederick R.,Fonseca, Kari R.,Liras, Spiros
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supporting information; experimental part
p. 7946 - 7949
(2010/08/03)
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- Substituted pyrazolopyrimidines
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The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions that include substituted heterobicyclic pyrimidines of Formula (I): wherein R1, R2, R3, R4, R5, X, W, and ring A are as defined herein; pharmaceutical compositions of substituted heterobicyclic pyrimidines of Formula (I); and their use in the treatment of chronic neurodegenerative diseases, neurotraumatic diseases, depression and/or diabetes. More particularly, the present invention relates to substituted pyrazolopyrimidines of Formula (I).
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Page/Page column 19
(2008/06/13)
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- PHENYL-SUBSTITUTED PYRAZOLOPYRIMIDINES
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The invention relates to novel phenyl-substituted pyrazolopyrimidines, to a method for the production thereof, and to their use for producing medicaments serving to improve perception, concentration, learning and/or memory.
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Page/Page column 35
(2008/06/13)
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- ALKYL-SUBSTITUTED PYRAZOLOPYRIMIDINES
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The invention relates to novel alkyl-substituted pyrazolopyrimidines, methods for the production thereof, and the use thereof for producing medicaments which improve awareness, concentration, learning capacity, and/or memory performance.
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Page/Page column 35
(2008/06/13)
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- PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease
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The invention provides compounds of Formula (I) the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, wherein A, P, J, x, and R10 are as defined herein; pharmaceutical compositions thereof; and methods of using the pharmaceutical compositions for the treatment of diseases, including, diabetes, including type 1 and type 2 diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, metabolic syndrome, and/or cardiovascular disease.
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