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Alexandre V. Ivachtchenko - One of the best experts on this subject based on the ideXlab platform.
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5-HT6 Receptor Antagonists. V. Structure – Activity Relationship of (4-Phenylsulfonyloxazol-5-yl)amines
Pharmaceutical Chemistry Journal, 2013Co-Authors: Alexandre V. Ivachtchenko, E. S. Golovina, Madina G. Kadieva, Oleg D. Mitkin, Ilya OkunAbstract:Both novel and previously reported (4-phenylsulfonyloxazol-5-yl)amine derivatives containing a substituted sulfonyl group were studied in order to discover highly active 5-HT6 Receptor antagonists. A new pharmacophore model of 5-HT6 Receptor antagonists was proposed based on the structure—5-HT6 antagonist activity relationship. It was established that the activity of the synthesized compounds depended strongly on the nature of the amine located vicinal to the sulfonyl. The most active ligands were methyl-(4-phenylsulfonyloxazol-5-yl)amines. Replacing the methyl by a bulkier alkyl radical and conversion to tertiary amines was accompanied by a dramatic reduction of their activity for 5-HT6 Receptors.
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5-HT6 Receptor antagonists. I. Screening of the library of various heterocyclic compounds containing an alkylsulfonyl moiety
Pharmaceutical Chemistry Journal, 2012Co-Authors: Alexandre V. Ivachtchenko, E. S. Golovina, Madina G. Kadieva, Oleg D. Mitkin, Sergey E. Tkachenko, Ilya OkunAbstract:High-throughput screening of a specific set (focused library) of heterocyclic compounds containing an alkylsulfonyl moiety (a total of 2827 compounds from 78 combinatorial libraries) was performed in order to discover highly effective 5-HT6 Receptor antagonists. The screening identified several compounds that exhibited pronounced inhibiting properties for 5-HT6 Receptors that enabled them to be used to develop new highly effective drugs for treating central nervous system disturbances. The structures of most antagonists corresponded to the PhM2 pharmacophore model, which confirmed its potential in the search for effective 5-HT6 Receptor antagonists. It was established that the structure of the substituent introduced in the vicinity of the sulfonyl moiety in the PhM2 ligands could affect their pharmacological activity, including the ability to block serotonin-induced 5-HT6 Receptor-mediated cell responses. In particular, bulky electron-donating substituents decreased the activity whereas a methylamino group increased statistically significantly the 5-HT6 antagonistic activity. Based on these findings, a new pharmacophore model for 5-HT6 antagonists, PhM3, was proposed. It was shown that compounds from the combinatorial libraries with a sulfonyl moiety separated from the heterocyclic and/or aromatic moiety by one (or more) methylenes and heterocyclic compounds containing an alkylsulfonyl moiety or endocyclic sulfonyl, (5-aryl-sulfonyl-3H-[1,2,3]triazol-4-yl)amines, and azoles substituted simultaneously by arylsulfonyl and alkylsulfonyl moieties all had low hit rates and were not promising for discovery of new 5-HT6 Receptor antagonists.
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synthesis and structure activity relationship sar of 5 7 disubstituted 3 phenylsulfonyl pyrazolo 1 5 a pyrimidin 2 yl methylamines as potent serotonin 5 ht6 Receptor 5 ht6r antagonists
Journal of Medicinal Chemistry, 2011Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Elena S Golovina, M G Kadieva, Volodymyr Kysil, Oleg Dmitrievich Mitkin, Ilya Matusovich OkunAbstract:Syntheses, biological evaluation as 5-HT6 Receptor (5-HT6R) antagonists, and structure–activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT6R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT6R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT6R ligands with modified ADME characteristics without gros...
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2 substituted 5 6 dimethyl 3 phenylsulfonyl pyrazolo 1 5 a pyrimidines new series of highly potent and specific serotonin 5 ht6 Receptor antagonists
European Journal of Medicinal Chemistry, 2011Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Elena S Golovina, M G Kadieva, Angela G Koryakova, Volodymyr Kysil, Oleg Dmitrievich Mitkin, Ilya Matusovich OkunAbstract:Abstract Syntheses, biological evaluation, and structure–activity relationships for a series of novel 2-substituted 3-benzenesulfonyl-5,6-dimethyl-pyrazolo[1,5-a]pyrimidines are disclosed. In spite of a wide, four orders of magnitude, SAR range (Ki varied from 260 pM to 2.96 μM), no significant correlation of 5-HT6R antagonistic potency was observed with major physiochemical characteristics, such as molecular weight, surface polar area, cLogP, or number of rotatable bonds. Statistically significant trend was only observed for size of substitute group, which was not enough to explain the deep SAR trend. Besides with the substitute group size, another factor that presumably plays a role in defining the compound potencies is a relative position of the heterocycle and sulfophenyl moieties. Among all synthesized derivatives, (3-benzenesulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 18 is the most potent (Ki = 260 pM) and extremely selective, 5000 to >50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT6 Receptor.
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3 phenylsulfonylcycloalkano e and d pyrazolo 1 5 a pyrimidin 2 yl amines potent and selective antagonists of the serotonin 5 ht6 Receptor
Journal of Medicinal Chemistry, 2010Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Dmitri E Dmitriev, Elena S Golovina, M G Kadieva, Angela G Koryakova, Volodymyr Kysil, Oleg Dmitrievich Mitkin, Ilya Matusovich Okun, Anton A VorobievAbstract:5-HT6 Receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this Receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 Receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the Receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 Receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B Receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.
María J. Ramírez - One of the best experts on this subject based on the ideXlab platform.
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Serotonin 5-HT6 Receptor Antagonists in Alzheimer's Disease: Therapeutic Rationale and Current Development Status.
CNS Drugs, 2016Co-Authors: Hilda Ferrero, Maite Solas, Paul T. Francis, María J. RamírezAbstract:Alzheimer’s disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT6 Receptor has received increasing attention, and a growing number of studies supported 5-HT6 Receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT6 Receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD. In addition to describing the available clinical evidence, this article also describes the purported biochemical and neurochemical mechanisms of action by which 5-HT6 Receptor antagonists could influence cognition, and the preclinical data supporting this therapeutic approach to AD. A large number of publications describing the development of ligands for this Receptor have come to light and preclinical data indicate the procognitive efficacy of 5-HT6 Receptor antagonists. Subsequently, the number of patents protecting 5-HT6 chemical entities has continuously grown. Some of these compounds have successfully undergone phase I clinical studies and have been further evaluated in clinical phase II trials with variable success. Phase II studies have also revealed the potential of combining 5-HT6 Receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been further developed into ongoing phase III clinical trials. Overall, 5-HT6 Receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.
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5-HT6 Receptors and Alzheimer's disease.
Alzheimer's Research & Therapy, 2013Co-Authors: María J. RamírezAbstract:During the past 20 years, the 5-HT6 Receptor has received increasing attention and become a promising target for improving cognition. Several studies with structurally different compounds have shown that not only antagonists but also 5-HT6 Receptor agonists improve learning and memory in animal models. A large number of publications describing the development of ligands for this Receptor have come to light, and it is now quite evident that 5-HT6 Receptors have great pharmaceutical potential in terms of related patents. However, 5-HT6 Receptor functionality is much more complex than initially defined. According to the existing data, different cellular pathways may be activated, depending on the drug being used. This article reviews preclinical and clinical evidence of the effects that 5-HT6 Receptor compounds have on cognition. In addition, the biochemical and neurochemical mechanisms of action through which 5-HT6 Receptor compounds can influence cognition will be described. Overall, several 5-HT6-targeted compounds can reasonably be regarded as powerful drug candidates for the treatment of Alzheimer's disease.
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5-HT6 Receptor signal transduction second messenger systems.
International Review of Neurobiology, 2010Co-Authors: Xavier Codony, Javier Burgueño, María J. Ramírez, José Miguel VelaAbstract:Publisher Summary The 5-HT6 Receptor belongs to the G-protein-coupled Receptor (GPCR) family. This chapter reviews some reported experimental approaches that can be used for a better functional characterization and classification of 5-HT6 Receptor ligands. The chapter summarizes the results obtained using some representative 5-HT6 Receptor agonists and antagonists. 5-HT6 Receptor functionality is being revealed to be much more complex than initially defined. Based on the existing data and depending on the agonist used, different selective Receptor active states that activate different cellular pathways may be achieved. Besides Gs-mediated cAMP formation, other messenger systems may be involved. The full characterization of the functional profile of 5-HT6 Receptor is still pending, and new players in the signaling cascade of 5-HT6 Receptor could take the stage in the near future.
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Signalling pathways associated with 5-HT6 Receptors: relevance for cognitive effects
The International Journal of Neuropsychopharmacology, 2009Co-Authors: Beatriz Marcos, Maite Solas, Maria Cabero, Bárbara Aisa, María J. RamírezAbstract:A growing body of evidence supports the use of serotonin 5-HT6 Receptor antagonists as a promising mechanism for treating cognitive dysfunction. We evaluated 5-HT6 Receptor expression and associated biochemical mechanisms in the hippocampus of rats that had been trained in the Morris water maze (MWM), a spatial learning task. Training in the MWM induces a down-regulation of 5-HT6 Receptor protein and mRNA Receptor expression. The learning procedure or the administration of the selective 5-HT6 Receptor antagonist SB-271046 induced an increase in pCREB1 levels while CREB2 levels were significantly reduced. However, although SB-271046 was able to improve retention in the MWM, no further changes in pCREB1 or CREB2 levels were found to be associated with the presence of the 5-HT6 Receptor antagonist during the learning procedure. The MWM procedure significantly increased pERK1/2 levels and interestingly, further increases were seen when treating with SB-271046 during the MWM. These results suggest that, in the hippocampus, biochemical pathways associated with pERK1/2 expression, and not with the CREB family of transcription factors, seem to be related to the cognitive-enhancing properties of 5-HT6 Receptor antagonists.
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Effects of 5-HT6 Receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat.
British Journal of Pharmacology, 2008Co-Authors: Beatriz Marcos, Tsu T. Chuang, Francisco J. Gil-bea, María J. RamírezAbstract:Background and purpose: The beneficial effect of 5-HT6 Receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT6 Receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits. Experimental approach: The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046. Key results: Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046. Conclusions and implications: These data suggest a potential therapeutic role of 5-HT6 Receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer's disease and schizophrenia. British Journal of Pharmacology (2008) 155, 434–440; doi:10.1038/bjp.2008.281; published online 14 July 2008
Ohdong Hwan - One of the best experts on this subject based on the ideXlab platform.
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antistress effects of rosa rugosa thunb on total sleep deprivation induced anxiety like behavior and cognitive dysfunction in rat possible mechanism of action of 5 ht6 Receptor antagonist
Journal of Medicinal Food, 2016Co-Authors: Ohdong HwanAbstract:Abstract Our previous results suggest that the Rosa rugosa Thunb. (family Rosaceae) alleviates endurance exercise-induced stress by decreasing oxidative stress levels. This study aimed to screen and identify the physiological antistress effects of an extract of R. rugosa (RO) on sleep deprivation–induced anxiety-like behavior and cognitive tests (in vivo) and tested for hippocampal CORT and monoamine levels (ex vivo), corticosterone (CORT)-induced injury, N-methyl-d-aspartate (NMDA) Receptor, and serotonin 6 (5-hydroxytryptamine 6, 5-HT6) Receptor activities (in vitro) in search of active principles and underlying mechanisms of action. We confirmed the antistress effects of RO in a sleep-deprived stress model in rat and explored the underlying mechanisms of its action. In conclusion, an R. rugosa extract showed efficacy and potential for use as an antistress therapy to treat sleep deprivation through its antagonism of the 5-HT6 Receptor and resulting inhibition of cAMP activity.
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Antistress Effects of Rosa rugosa Thunb. on Total Sleep Deprivation–Induced Anxiety-Like Behavior and Cognitive Dysfunction in Rat: Possible Mechanism of Action of 5-HT6 Receptor Antagonist
Journal of Medicinal Food, 2016Co-Authors: Naju-ryun, Ohdong Hwan, Ohdool-ri, Hanseulhee, Kimyu-jin, Choieunjin, Baedonghyuck, Leeyoo-hyun, Kimsunoh, JunwoojinAbstract:Abstract Our previous results suggest that the Rosa rugosa Thunb. (family Rosaceae) alleviates endurance exercise-induced stress by decreasing oxidative stress levels. This study aimed to screen and identify the physiological antistress effects of an extract of R. rugosa (RO) on sleep deprivation–induced anxiety-like behavior and cognitive tests (in vivo) and tested for hippocampal CORT and monoamine levels (ex vivo), corticosterone (CORT)-induced injury, N-methyl-d-aspartate (NMDA) Receptor, and serotonin 6 (5-hydroxytryptamine 6, 5-HT6) Receptor activities (in vitro) in search of active principles and underlying mechanisms of action. We confirmed the antistress effects of RO in a sleep-deprived stress model in rat and explored the underlying mechanisms of its action. In conclusion, an R. rugosa extract showed efficacy and potential for use as an antistress therapy to treat sleep deprivation through its antagonism of the 5-HT6 Receptor and resulting inhibition of cAMP activity.
Ilya Matusovich Okun - One of the best experts on this subject based on the ideXlab platform.
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synthesis and structure activity relationship sar of 5 7 disubstituted 3 phenylsulfonyl pyrazolo 1 5 a pyrimidin 2 yl methylamines as potent serotonin 5 ht6 Receptor 5 ht6r antagonists
Journal of Medicinal Chemistry, 2011Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Elena S Golovina, M G Kadieva, Volodymyr Kysil, Oleg Dmitrievich Mitkin, Ilya Matusovich OkunAbstract:Syntheses, biological evaluation as 5-HT6 Receptor (5-HT6R) antagonists, and structure–activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT6R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT6R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT6R ligands with modified ADME characteristics without gros...
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2 substituted 5 6 dimethyl 3 phenylsulfonyl pyrazolo 1 5 a pyrimidines new series of highly potent and specific serotonin 5 ht6 Receptor antagonists
European Journal of Medicinal Chemistry, 2011Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Elena S Golovina, M G Kadieva, Angela G Koryakova, Volodymyr Kysil, Oleg Dmitrievich Mitkin, Ilya Matusovich OkunAbstract:Abstract Syntheses, biological evaluation, and structure–activity relationships for a series of novel 2-substituted 3-benzenesulfonyl-5,6-dimethyl-pyrazolo[1,5-a]pyrimidines are disclosed. In spite of a wide, four orders of magnitude, SAR range (Ki varied from 260 pM to 2.96 μM), no significant correlation of 5-HT6R antagonistic potency was observed with major physiochemical characteristics, such as molecular weight, surface polar area, cLogP, or number of rotatable bonds. Statistically significant trend was only observed for size of substitute group, which was not enough to explain the deep SAR trend. Besides with the substitute group size, another factor that presumably plays a role in defining the compound potencies is a relative position of the heterocycle and sulfophenyl moieties. Among all synthesized derivatives, (3-benzenesulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 18 is the most potent (Ki = 260 pM) and extremely selective, 5000 to >50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT6 Receptor.
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3 phenylsulfonylcycloalkano e and d pyrazolo 1 5 a pyrimidin 2 yl amines potent and selective antagonists of the serotonin 5 ht6 Receptor
Journal of Medicinal Chemistry, 2010Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Dmitri E Dmitriev, Elena S Golovina, M G Kadieva, Angela G Koryakova, Volodymyr Kysil, Oleg Dmitrievich Mitkin, Ilya Matusovich Okun, Anton A VorobievAbstract:5-HT6 Receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this Receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 Receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the Receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 Receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B Receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.
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solution phase parallel synthesis of substituted 3 phenylsulfonyl 1 2 3 triazolo 1 5 a quinazolines selective serotonin 5 ht6 Receptor antagonists
ACS Combinatorial Science, 2010Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Elena S Golovina, M G Kadieva, Angela G Koryakova, Oleg Dmitrievich Mitkin, Ilya Matusovich Okun, Sergiy M Kovalenko, Irina M Ravnyeyko, Oleg V ZarembaAbstract:Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure with a 5-HT6 Receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive binding. We have found highly active and selective 5-HT6R antagonists. The most active 5-HT6R antagonists have IC50 <100 nM in a functional assay, and Ki <10 nM in a binding assay, which is 100 times higher than the activity with respect to other serotonin Receptors.
Sergey E. Tkachenko - One of the best experts on this subject based on the ideXlab platform.
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5-HT6 Receptor antagonists. I. Screening of the library of various heterocyclic compounds containing an alkylsulfonyl moiety
Pharmaceutical Chemistry Journal, 2012Co-Authors: Alexandre V. Ivachtchenko, E. S. Golovina, Madina G. Kadieva, Oleg D. Mitkin, Sergey E. Tkachenko, Ilya OkunAbstract:High-throughput screening of a specific set (focused library) of heterocyclic compounds containing an alkylsulfonyl moiety (a total of 2827 compounds from 78 combinatorial libraries) was performed in order to discover highly effective 5-HT6 Receptor antagonists. The screening identified several compounds that exhibited pronounced inhibiting properties for 5-HT6 Receptors that enabled them to be used to develop new highly effective drugs for treating central nervous system disturbances. The structures of most antagonists corresponded to the PhM2 pharmacophore model, which confirmed its potential in the search for effective 5-HT6 Receptor antagonists. It was established that the structure of the substituent introduced in the vicinity of the sulfonyl moiety in the PhM2 ligands could affect their pharmacological activity, including the ability to block serotonin-induced 5-HT6 Receptor-mediated cell responses. In particular, bulky electron-donating substituents decreased the activity whereas a methylamino group increased statistically significantly the 5-HT6 antagonistic activity. Based on these findings, a new pharmacophore model for 5-HT6 antagonists, PhM3, was proposed. It was shown that compounds from the combinatorial libraries with a sulfonyl moiety separated from the heterocyclic and/or aromatic moiety by one (or more) methylenes and heterocyclic compounds containing an alkylsulfonyl moiety or endocyclic sulfonyl, (5-aryl-sulfonyl-3H-[1,2,3]triazol-4-yl)amines, and azoles substituted simultaneously by arylsulfonyl and alkylsulfonyl moieties all had low hit rates and were not promising for discovery of new 5-HT6 Receptor antagonists.
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synthesis and structure activity relationship sar of 5 7 disubstituted 3 phenylsulfonyl pyrazolo 1 5 a pyrimidin 2 yl methylamines as potent serotonin 5 ht6 Receptor 5 ht6r antagonists
Journal of Medicinal Chemistry, 2011Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Elena S Golovina, M G Kadieva, Volodymyr Kysil, Oleg Dmitrievich Mitkin, Ilya Matusovich OkunAbstract:Syntheses, biological evaluation as 5-HT6 Receptor (5-HT6R) antagonists, and structure–activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT6R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT6R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT6R ligands with modified ADME characteristics without gros...
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2 substituted 5 6 dimethyl 3 phenylsulfonyl pyrazolo 1 5 a pyrimidines new series of highly potent and specific serotonin 5 ht6 Receptor antagonists
European Journal of Medicinal Chemistry, 2011Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Elena S Golovina, M G Kadieva, Angela G Koryakova, Volodymyr Kysil, Oleg Dmitrievich Mitkin, Ilya Matusovich OkunAbstract:Abstract Syntheses, biological evaluation, and structure–activity relationships for a series of novel 2-substituted 3-benzenesulfonyl-5,6-dimethyl-pyrazolo[1,5-a]pyrimidines are disclosed. In spite of a wide, four orders of magnitude, SAR range (Ki varied from 260 pM to 2.96 μM), no significant correlation of 5-HT6R antagonistic potency was observed with major physiochemical characteristics, such as molecular weight, surface polar area, cLogP, or number of rotatable bonds. Statistically significant trend was only observed for size of substitute group, which was not enough to explain the deep SAR trend. Besides with the substitute group size, another factor that presumably plays a role in defining the compound potencies is a relative position of the heterocycle and sulfophenyl moieties. Among all synthesized derivatives, (3-benzenesulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 18 is the most potent (Ki = 260 pM) and extremely selective, 5000 to >50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT6 Receptor.
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3 phenylsulfonylcycloalkano e and d pyrazolo 1 5 a pyrimidin 2 yl amines potent and selective antagonists of the serotonin 5 ht6 Receptor
Journal of Medicinal Chemistry, 2010Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Dmitri E Dmitriev, Elena S Golovina, M G Kadieva, Angela G Koryakova, Volodymyr Kysil, Oleg Dmitrievich Mitkin, Ilya Matusovich Okun, Anton A VorobievAbstract:5-HT6 Receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this Receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 Receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the Receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 Receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B Receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.
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solution phase parallel synthesis of substituted 3 phenylsulfonyl 1 2 3 triazolo 1 5 a quinazolines selective serotonin 5 ht6 Receptor antagonists
ACS Combinatorial Science, 2010Co-Authors: Alexandre V. Ivachtchenko, Sergey E. Tkachenko, Elena S Golovina, M G Kadieva, Angela G Koryakova, Oleg Dmitrievich Mitkin, Ilya Matusovich Okun, Sergiy M Kovalenko, Irina M Ravnyeyko, Oleg V ZarembaAbstract:Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure with a 5-HT6 Receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive binding. We have found highly active and selective 5-HT6R antagonists. The most active 5-HT6R antagonists have IC50 <100 nM in a functional assay, and Ki <10 nM in a binding assay, which is 100 times higher than the activity with respect to other serotonin Receptors.
