Synthesis and SAR of pyridazinone-substituted phenylalanine amide alpha4 integrin antagonists.
Structural modification and cellular adhesion inhibition activities of pyridazinone-substituted phenylalanine amide alpha(4) integrin antagonists are described. Functionality requirements for the arylamide moiety and the carboxylic acid group were demonstrated. The study also revealed novel structure-activity relationships (SAR) for arylated pyridazinones. A correlation between bioavailability and permeability was also explored. A selected compound showed effectiveness in a mouse leukocytosis study.
Gong
Yong
Y
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Welsh & McKean Roads, PO Box 776, Spring House, PA 19477-0776, USA.
Kent Barbay
J
J
Kimball
Edward S
ES
Santulli
Rosemary J
RJ
Carolyn Fisher
M
M
Dyatkin
Alexey B
AB
Miskowski
Tamara A
TA
Hornby
Pamela J
PJ
He
Wei
W
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D039441:Integrin alpha4 / Q000737:chemistry / Q000378:metabolism*; D007408:Intestinal Absorption; D007964:Leukocytosis / Q000188:drug therapy; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D011724:Pyridazines; D039441:Integrin alpha4; D010649:Phenylalanine