Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists.
A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics.
Reger
Thomas S
TS
Department of Medicinal Chemistry, Merck Research Laboratories, San Diego, CA 92121, USA. thomas_reger@merck.com
Zunic
Jasmine
J
Stock
Nicholas
N
Wang
Bowei
B
Smith
Nicholas D
ND
Munoz
Benito
B
Green
Mitchell D
MD
Gardner
Michael F
MF
James
Joyce P
JP
Chen
Weichao
W
Alves
Kenneth
K
Si
Qian
Q
Treonze
Kelly M
KM
Lingham
Russell B
RB
Mumford
Richard A
RA
D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011392:Proline / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D051381:Rats
D004151:Dipeptides; D006571:Heterocyclic Compounds; D039041:Integrin alpha4beta1; D011392:Proline