Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors containing sulfonamides of 5,6-disubstituted anthranilic acids.
A series of aryl sulfonamides of 5,6-disubstituted anthranilic acids were identified as potent inhibitors of methionine aminopeptidase-2 (MetAP2). Small alkyl groups and 3-furyl were tolerated at the 5-position of anthranilic acid, while -OCH(3), CH(3), and Cl were found optimal for the 6-position. Placement of 2-aminoethoxy group at the 6-position enabled interaction with the second Mn(2+) but did not result in enhancement in potency. Introduction of a tertiary amino moiety at the ortho-position of the sulfonyl phenyl ring gave reduced protein binding and improved cellular activity, but led to lower oral bioavailability.
Wang
Gary T
GT
Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gary.t.wang@abbott.com
Mantei
Robert A
RA
Kawai
Megumi
M
Tedrow
Jason S
JS
Barnes
David M
DM
Wang
Jieyi
J
Zhang
Qian
Q
Lou
Pingping
P
Garcia
Lora A
LA
Bouska
Jennifer
J
Yates
Melinda
M
Park
Chang
C
Judge
Russell A
RA
Lesniewski
Richard
R
Sheppard
George S
GS
Bell
Randy L
RL
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007854:Lead / Q000737:chemistry*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
D013449:Sulfonamides; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007854:Lead; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases