Benzenesulfonamide indole inhibitors of cytosolic phospholipase A2alpha: optimization of in vitro potency and rat pharmacokinetics for oral efficacy.
The synthesis and structure-activity relationship of a series of benzenesulfonamide indole inhibitors of cPLA(2)alpha are described. Substitution of the benzenesulfonamide led to analogues with 50-fold improvement in potency versus the unsubstituted benzenesulfonamide lead compound. Rat pharmacokinetics in a minimal formulation was used to prioritize compounds, leading to the discovery of a potent inhibitor of cPLA(2)alpha with oral efficacy in models of rat carrageenan paw edema and Ascaris suum airway challenge in naturally sensitized sheep.
Lee
Katherine L
KL
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. klee@wyeth.com
Behnke
Mark L
ML
Foley
Megan A
MA
Chen
Lihren
L
Wang
Weiheng
W
Vargas
Richard
R
Nunez
Jill
J
Tam
Steve
S
Mollova
Nevena
N
Xu
Xin
X
Shen
Marina W H
MW
Ramarao
Manjunath K
MK
Goodwin
Debra G
DG
Nickerson-Nutter
Cheryl L
CL
Abraham
William M
WM
Williams
Cara
C
Clark
James D
JD
McKew
John C
JC
D000284:Administration, Oral; D000818:Animals; D001196:Ascariasis / Q000188:drug therapy / Q000469:parasitology; D017165:Ascaris suum / Q000502:physiology; D002151:Calorimetry; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015394:Molecular Structure; D051381:Rats; D012756:Sheep; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013696:Temperature; D000096926:Benzenesulfonamides
D054513:Group IV Phospholipases A2; D007211:Indoles; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C030374:indole