Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity |
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Authors: | Ashton W T Sisco R M Kieczykowski G R Yang Y T Yudkovitz J B Cui J Mount G R Ren R N Wu T J Shen X Lyons K A Mao A H Carlin J R Karanam B V Vincent S H Cheng K Goulet M T |
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Affiliation: | Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, NJ 07065-0900, Rahway, USA |
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Abstract: | Stereospecific introduction of a methyl group to the indole-3-side chain enhanced activity in our tryptamine-derived series of GnRH receptor antagonists. Further improvements were achieved by variation of the bicyclic amino moiety of the tertiary amide and by adjustment of the tether length to a pyridine or pyridone terminus. These modifications culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys. |
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