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

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 3; pp. 1421 - 1426
• Main Authors: Tripathy, Rabindranath, McHugh, Robert J., Bacon, Edward R., Salvino, Joseph M., Morton, George C., Aimone, Lisa D., Huang, Zeck, Mathiasen, Joanne R., DiCamillo, Amy, Huffman, Mark J., McKenna, Beth A., Kopec, Karla, Lu, Lily D., Qian, Jie, Angeles, Thelma S., Connors, Thomas, Spais, Chrysanthe, Holskin, Beverly, Duzic, Emir, Schaffhauser, Hervé, Rossé, Gerard C.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-02-2012; Elsevier
• Subjects: 5-HT6 receptor antagonist; Animal models; Animals; antagonists; Bioavailability; Biological and medical sciences; Brain; Brain - drug effects; Cognition; Cognitive dysfunction; Dogs; Enantiomers; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Inhibitory Concentration 50; Learning; Liver; Medical sciences; Memory; Mice; Microsomes; Microsomes, Liver - drug effects; Molecular Structure; Neurotransmission; pharmacology; Pharmacology. Drug treatments; Pharmacophore model; pharmacophores; pyridines; Rat social recognition test; Rats; Receptors, Serotonin; Salts; scaffolds; Serotonin; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacokinetics; Serotonin Antagonists - pharmacology; Serotonin S6 receptors; Social interactions; Stereoisomerism; Sulfones - chemistry; Sulfones - pharmacology; tetrahydropyridines; Cognition; 5-HT6 receptor antagonist; Pharmacophore model; Rat social recognition test; Cognitive dysfunction; Cognitive disorder; Rat; Rodentia; 5-HT6 serotonin receptor; Selectivity; Biological activity; Vertebrata; Furopyridin derivatives; Mammalia; Animal; Molecular model; Antagonist; 5-HT; receptor antagonist; Recognition; Public health
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.026

Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine6 (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 ∼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.