Discovery of a new class of macrocyclic antagonists to the human motilin receptor.
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.
Marsault
Eric
E
Tranzyme Pharma Inc., 3001, 12e Avenue Nord, Sherbrooke, PQ, Canada, J1H 5N4. emarsault@tranzyme.com
Hoveyda
Hamid R
HR
Peterson
Mark L
ML
Saint-Louis
Carl
C
Landry
Annick
A
Vézina
Martin
M
Ouellet
Luc
L
Wang
Zhigang
Z
Ramaseshan
Mahesh
M
Beaubien
Sylvie
S
Benakli
Kamel
K
Beauchemin
Sophie
S
Déziel
Robert
R
Peeters
Theo
T
Fraser
Graeme L
GL
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
D047028:Macrocyclic Compounds; D009842:Oligopeptides; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor