Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity (II): Optimization of the C3 amino substituent.
Analogs of the previously reported 1,5-benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonist 1 were prepared which explore substitution and/or replacement of the C-3 phenyl urea moiety. Agonist efficacy on the isolated guinea pig gallbladder (GPGB) was retained with a variety of substituted ureas and amide analogs. Three compounds were identified which were orally active in the mouse gallbladder emptying assay (MGBE). The 2-indolamide (52) and N-(carboxymethyl)-2-indolamide (54) derivatives had improved affinity for the human CCK-A receptor but reduced agonist efficacy on the GPGB. Neither indolamide was orally active in a rat feeding assay. In contrast, the (3-carboxyphenyl)urea derivative (29, GW7854) had moderately increased affinity for the human CCK-B receptor but was a potent full agonist on the GPGB and was orally active in both the MGBE and rat feeding assays. GW7854 was a full agonist (EC50 = 60 nM) for calcium mobilization on CHO K1 cells expressing hCCK-A receptors and a potent antagonist of CCK-8 (pA2 = 9.1) on CHO K1 cells expressing hCCK-B receptors. GW7854 is a potent mixed CCK-A agonist/CCK-B antagonist which is orally active in two in vivo models of CCK-A-mediated agonist activity.
Hirst
G C
GC
Department of Medicinal Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
Aquino
C
C
Birkemo
L
L
Croom
D K
DK
Dezube
M
M
Dougherty
R W
RW
Ervin
G N
GN
Grizzle
M K
MK
Henke
B
B
James
M K
MK
Johnson
M F
MF
Momtahen
T
T
Queen
K L
KL
Sherrill
R G
RG
Szewczyk
J
J
Willson
T M
TM
Sugg
E E
EE
D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D005247:Feeding Behavior / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D051381:Rats; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D001067:Appetite Depressants; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; D002118:Calcium