Disubstituted indazoles as potent antagonists of the integrin alpha(v)beta(3).
A new series of indazole-containing alpha(v)beta(3) integrin antagonists is described. Starting with lead compound 18a, variations in a number of structural features were explored with respect to inhibition of the binding of beta(3)-transfected 293 cells to fibrinogen and to selectivity for alpha(v)beta(3) over GPIIbIIIa, another RGD-binding integrin. Indazoles attached to a 2-aminopyridine or 2-aminoimidazole by a propylene linker at the indazole 1-position and to a diaminopropionate derivative via a 5-carboxylate amide provided the best potency with moderate selectivity. Several differences in the SAR of the diaminopropionate moiety were observed between this series and a series of isoxazoline-based selective GPIIbIIIa antagonists. Compound 34a (SM256) was a potent antagonist of alpha(v)beta(3) (IC(50) 2.3 nM) with 9-fold selectivity over GPIIbIIIa.
Batt
D G
DG
DuPont Pharmaceuticals Company, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. battdg@a1.lldmpc.umc.dupont.com
Petraitis
J J
JJ
Houghton
G C
GC
Modi
D P
DP
Cain
G A
GA
Corjay
M H
MH
Mousa
S A
SA
Bouchard
P J
PJ
Forsythe
M S
MS
Harlow
P P
PP
Barbera
F A
FA
Spitz
S M
SM
Wexler
R R
RR
Jadhav
P K
PK
D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D007191:Indazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019030:Receptors, Vitronectin; D005340:Fibrinogen