Discovery of a potent and novel motilin agonist.
A novel series of dihydro- and tetrahydrotriazolopyridazine-1,3-dione-based amino acid derivatives were identified as very potent motilin receptor agonists. Incorporating one additional phenylethyl glycinamide subunit to 1 (EC(50) = 660 nM) was found to improve in vitro potency approximately 3000-fold, resulting in compound 10 (EC(50) = 0.22 nM). The more potent enantiomer 11A has an EC(50) of 0.047 nM in the motilin receptor functional assay and a K(i) of 0.7 nM in the binding assay. In addition, compound 11A was shown to have a significantly reduced tendency to cause receptor desensitization as compared with the motilin receptor agonist ABT-229.
Li
James J
JJ
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08643-5400, USA. james.li@bms.com
Chao
Hann-Guang
HG
Wang
Haixia
H
Tino
Joseph A
JA
Lawrence
R Michael
RM
Ewing
William R
WR
Ma
Zhengping
Z
Yan
Mujing
M
Slusarchyk
Dorothy
D
Seethala
Ramakrishna
R
Sun
Huabin
H
Li
Danshi
D
Burford
Neil T
NT
Stoffel
Robert H
RH
Salyan
Mary Ellen
ME
Li
Cindy Y
CY
Witkus
Michael
M
Zhao
Ning
N
Rich
Adam
A
Gordon
David A
DA
D020013:Calcium Signaling / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D009037:Motilin / Q000819:agonists*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D011724:Pyridazines; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; D014230:Triazoles; C050802:motilin receptor; D009037:Motilin