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Bioorg Med Chem Lett. 2009 Oct 1;19(19):5787-90. doi: 10.1016/j.bmcl.2009.07.134. Epub 2009 Aug 6.

Novel CGRP receptor antagonists through a design strategy of target simplification with addition of molecular flexibility.

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Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, USA.


A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP Ki=0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.

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