The design and synthesis of novel orally active inhibitors of AP-1 and NF-kappaB mediated transcriptional activation. SAR of in vitro and in vivo studies.
We have developed novel orally active quinazoline analogues as inhibitors of AP-1 and NF-kappaB mediated transcriptional activation. Among the derivatives prepared, 1-[2-(2-thienyl)quinazolin-4-ylamino]-3-methyl-3-pyrroline-2,5-dione (10) showed significant activity in an adjuvant-induced arthritis rat model by reducing the swelling by 65% in the non-injected foot. The synthesis, structure-activity relationship, and in vivo activity are described.
Celgene, 4550 Towne Centre Court, San Diego, CA 92121, USA. mpalanki@celgene.com
Moorthy S S
MS
Palanki
Paul E
PE
Erdman
Minghuan
M
Ren
Mark
M
Suto
Brydon L
BL
Bennett
Anthony
A
Manning
Lynn
L
Ransone
Cheryl
C
Spooner
Sonal
S
Desai
Arnie
A
Ow
Ryuichi
R
Totsuka
Peter
P
Tsao
Wataru
W
Toriumi
D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation / Q000187:drug effects*
D016328:NF-kappa B; D011799:Quinazolines; D018808:Transcription Factor AP-1