Synthesis and characterization of nonsteroidal glucocorticoid receptor modulators for multiple myeloma.
Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.
Hudson
Andrew R
AR
Discovery Research, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121, USA. ahudson@ligand.com
Roach
Steven L
SL
Higuchi
Robert I
RI
Phillips
Dean P
DP
Bissonnette
Reid P
RP
Lamph
William W
WW
Yen
Jean
J
Li
Yongkai
Y
Adams
Mark E
ME
Valdez
Lino J
LJ
Vassar
Angie
A
Cuervo
Catalina
C
Kallel
E Adam
EA
Gharbaoui
Catherine J
CJ
Mais
Dale E
DE
Miner
Jeffrey N
JN
Marschke
Keith B
KB
Rungta
Deepa
D
Negro-Vilar
Andrés
A
Zhi
Lin
L
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D018161:Receptors, Mineralocorticoid / Q000819:agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001578:Benzopyrans; D000451:Mineralocorticoid Receptor Antagonists; D011804:Quinolines; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D003907:Dexamethasone