title: Discovery of a new class of macrocyclic antagonists to the human motilin receptor.
abstract: A novel class of macrocyclic peptidomimetics was identified and optimized as potent antagonists to the human motilin receptor (hMOT-R). Well-defined structure-activity relationships allowed for rapid optimization of potency that eventually led to high affinity antagonists to hMOT-R. Potency and antagonist functional activity were confirmed both in functional and cell-based assays, as well as on isolated rabbit intestinal smooth muscle strips. Rapid access to this novel class of macrocyclic target structures was made possible through two efficient and complementary solid-phase parallel synthetic approaches, both of which are reported herein.
authors.affiliation: Tranzyme Pharma Inc., 3001, 12e Avenue Nord, Sherbrooke, PQ, Canada, J1H 5N4. emarsault@tranzyme.com
authors.forename: Eric
authors.initials: E
authors.lastname: Marsault
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Hoveyda
authors.forename: Mark L
authors.initials: ML
authors.lastname: Peterson
authors.forename: Carl
authors.initials: C
authors.lastname: Saint-Louis
authors.forename: Annick
authors.initials: A
authors.lastname: Landry
authors.forename: Martin
authors.initials: M
authors.lastname: Vézina
authors.forename: Luc
authors.initials: L
authors.lastname: Ouellet
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Mahesh
authors.initials: M
authors.lastname: Ramaseshan
authors.forename: Sylvie
authors.initials: S
authors.lastname: Beaubien
authors.forename: Kamel
authors.initials: K
authors.lastname: Benakli
authors.forename: Sophie
authors.initials: S
authors.lastname: Beauchemin
authors.forename: Robert
authors.initials: R
authors.lastname: Déziel
authors.forename: Theo
authors.initials: T
authors.lastname: Peeters
authors.forename: Graeme L
authors.initials: GL
authors.lastname: Fraser
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004386:Duodenum / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D047028:Macrocyclic Compounds; D009842:Oligopeptides; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor