Optimization of alkylidene hydrazide based human glucagon receptor antagonists. Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide.
Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-cyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC(50) = 2.3 nM, K(B) = 760 pM) and of the isolated rat receptor (IC(50) = 430 pM, K(B) = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K(i) = 14 nM). This compound was orally available in dogs (F(po) = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.
Madsen
Peter
P
Department of Medicinal Chemistry, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. pem@novonordisk.com
Ling
Anthony
A
Plewe
Michael
M
Sams
Christian K
CK
Knudsen
Lotte B
LB
Sidelmann
Ulla G
UG
Ynddal
Lars
L
Brand
Christian L
CL
Andersen
Birgitte
B
Murphy
Douglas
D
Teng
Min
M
Truesdale
Larry
L
Kiel
Dan
D
May
John
J
Kuki
Atsuo
A
Shi
Shenghua
S
Johnson
Michael D
MD
Teston
Kimberly Ann
KA
Feng
Jun
J
Lakis
James
J
Anderes
Kenna
K
Gregor
Vlad
V
Lau
Jesper
J
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured; D004285:Dogs; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000096:biosynthesis; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C470208:(1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene)hydrazide; D006834:Hydrazines; D007211:Indoles; D018027:Receptors, Glucagon; D005934:Glucagon; D005947:Glucose