Bioisosteric replacement of anilide with benzoxazole: potent and orally bioavailable antagonists of VLA-4.
We have designed and synthesized a series of heterocyclic bioisosteres for an anilide based on molecular modeling. Excellent potency was retained in the benzoxazole and the benzimidazole derivatives, where a hydrogen bond acceptor is appropriately positioned to mimic the amide bond oxygen. The deletion of the hydrogen bond donor (N-H) led to improved lipophilicity and bioavailability. In the process, 9a was identified as a potent, specific, and bioavailable VLA-4 antagonist, while 9c was found to be a potent and bioavailable dual antagonist of VLA-4 and alpha(4)beta(7).
Lin
Linus S
LS
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
Lanza
Thomas J
TJ
Castonguay
Laurie A
LA
Kamenecka
Theodore
T
McCauley
Ermenegilda
E
Van Riper
Gail
G
Egger
Linda A
LA
Mumford
Richard A
RA
Tong
Xinchun
X
MacCoss
Malcolm
M
Schmidt
John A
JA
Hagmann
William K
WK
D000813:Anilides / Q000737:chemistry*; D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry*; D001682:Biological Availability; D006860:Hydrogen Bonding; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051381:Rats
D000813:Anilides; D001583:Benzoxazoles; D039041:Integrin alpha4beta1