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Mark J Huffman - One of the best experts on this subject based on the ideXlab platform.
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discovery of 7 arylsulfonyl 1 2 3 4 4a 9a hexahydro benzo 4 5 furo 2 3 c pyridines identification of a potent and selective 5 ht6 receptor antagonist showing activity in rat Social Recognition Test
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Rabindranath Tripathy, Robert J Mchugh, Edward R Bacon, Joseph M Salvino, George C Morton, Lisa D Aimone, Zeck Huang, Joanne R Mathiasen, Amy Dicamillo, Mark J HuffmanAbstract:Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ∼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat Social Recognition Test.
Rabindranath Tripathy - One of the best experts on this subject based on the ideXlab platform.
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discovery of 7 arylsulfonyl 1 2 3 4 4a 9a hexahydro benzo 4 5 furo 2 3 c pyridines identification of a potent and selective 5 ht6 receptor antagonist i showing activity in rat Social Recognition Test
ChemInform, 2012Co-Authors: Rabindranath TripathyAbstract:The key step in the synthesis of (I) is the CuI-mediated coupling reaction between methoxy-isopropyloxybenzenethiol and 7-iodo-hexahydro-benzofuropyridine followed by S-oxidation with MCPBA.
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discovery of 7 arylsulfonyl 1 2 3 4 4a 9a hexahydro benzo 4 5 furo 2 3 c pyridines identification of a potent and selective 5 ht6 receptor antagonist showing activity in rat Social Recognition Test
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Rabindranath Tripathy, Robert J Mchugh, Edward R Bacon, Joseph M Salvino, George C Morton, Lisa D Aimone, Zeck Huang, Joanne R Mathiasen, Amy Dicamillo, Mark J HuffmanAbstract:Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ∼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat Social Recognition Test.
Robert J Mchugh - One of the best experts on this subject based on the ideXlab platform.
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discovery of 7 arylsulfonyl 1 2 3 4 4a 9a hexahydro benzo 4 5 furo 2 3 c pyridines identification of a potent and selective 5 ht6 receptor antagonist showing activity in rat Social Recognition Test
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Rabindranath Tripathy, Robert J Mchugh, Edward R Bacon, Joseph M Salvino, George C Morton, Lisa D Aimone, Zeck Huang, Joanne R Mathiasen, Amy Dicamillo, Mark J HuffmanAbstract:Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ∼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat Social Recognition Test.
Amy Dicamillo - One of the best experts on this subject based on the ideXlab platform.
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discovery of 7 arylsulfonyl 1 2 3 4 4a 9a hexahydro benzo 4 5 furo 2 3 c pyridines identification of a potent and selective 5 ht6 receptor antagonist showing activity in rat Social Recognition Test
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Rabindranath Tripathy, Robert J Mchugh, Edward R Bacon, Joseph M Salvino, George C Morton, Lisa D Aimone, Zeck Huang, Joanne R Mathiasen, Amy Dicamillo, Mark J HuffmanAbstract:Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ∼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat Social Recognition Test.
Joanne R Mathiasen - One of the best experts on this subject based on the ideXlab platform.
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discovery of 7 arylsulfonyl 1 2 3 4 4a 9a hexahydro benzo 4 5 furo 2 3 c pyridines identification of a potent and selective 5 ht6 receptor antagonist showing activity in rat Social Recognition Test
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Rabindranath Tripathy, Robert J Mchugh, Edward R Bacon, Joseph M Salvino, George C Morton, Lisa D Aimone, Zeck Huang, Joanne R Mathiasen, Amy Dicamillo, Mark J HuffmanAbstract:Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ∼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat Social Recognition Test.