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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
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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

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. Huffman, …
Bioorganic & medicinal chemistry letters, v 22(3), pp 1421-1426
01 Feb 2012
DOI: https://doi.org/10.1016/j.bmcl.2011.12.026
PMID: 22226656
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.7270/q20z73r1View
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Abstract

Chemistry Chemistry, Medicinal Chemistry, Organic Life Sciences & Biomedicine Pharmacology & Pharmacy Physical Sciences Science & Technology
Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT6) 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-HT6 receptor antagonists. Despite good activity against 5-HT6 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 similar to 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-HT6. Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT6 antagonists with improved PK profiles in rat. A potent, selective 5-HT6R 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. (C) 2011 Elsevier Ltd. All rights reserved.

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Web of Science research areas
Chemistry, Medicinal
Chemistry, Organic
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