Solid-phase synthesis of dual alpha4beta1/alpha4beta7 integrin antagonists: two scaffolds with overlapping pharmacophores.
Two structural classes of dual alpha4beta1/alpha4beta7 integrin antagonists were investigated via solid-phase parallel synthesis. Using an acylated amino acid backbone, lead compounds containing biphenylalanine or tyrosine carbamate scaffolds were optimized for inhibition of alpha4beta1/VCAM and alpha4beta7/MAdCAM. A comparison of the structure-activity relationships in the inhibition of the alpha4beta7/MAdCAM interaction for substituted amines employed in both scaffolds suggests a similar binding mode for the compounds.
Castanedo
Georgette M
GM
Department of Bioorganic Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
Sailes
Fredrick C
FC
Dubree
Nathan J P
NJ
Nicholas
John B
JB
Caris
Lisa
L
Clark
Kevin
K
Keating
Susan M
SM
Beresini
Maureen H
MH
Chiu
Henry
H
Fong
Sherman
S
Marsters
James C
JC
Jackson
David Y
DY
Sutherlin
Daniel P
DP
D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D039041:Integrin alpha4beta1; D016023:Integrins; C071777:integrin alpha4beta7