1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives. |
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| Authors: | L Jeppesen P H Olesen L Hansen M J Sheardown C Thomsen T Rasmussen A F Jensen M S Christensen K Rimvall J S Ward C Whitesitt D O Calligaro F P Bymaster N W Delapp C C Felder H E Shannon P Sauerberg |
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| Affiliation: | Novo Nordisk A/S, Health Care Discovery, Novo Nordisk Park, DK-2760 Malov, Denmark. |
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| Abstract: | Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite. |
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