title: Novel CGRP receptor antagonists through a design strategy of target simplification with addition of molecular flexibility.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.forename: Kathy M
authors.initials: KM
authors.lastname: Schirripa
authors.forename: June J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Amy G
authors.initials: AG
authors.lastname: Quigley
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Bednar
authors.forename: John F
authors.initials: JF
authors.lastname: Fay
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.forename: Eric L
authors.initials: EL
authors.lastname: Moore
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.forename: Shane
authors.initials: S
authors.lastname: Roller
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D051381:Rats; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D018015:Receptors, Calcitonin Gene-Related Peptide; D013141:Spiro Compounds