Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.
A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.
Crosignani
Stefano
S
Merck Serono International S.A., 9 chemin des Mines, Geneva, Switzerland.
Page
Patrick
P
Missotten
Marc
M
Colovray
Véronique
V
Cleva
Christophe
C
Arrighi
Jean-François
JF
Atherall
John
J
Macritchie
Jackie
J
Martin
Thierry
T
Humbert
Yves
Y
Gaudet
Marilène
M
Pupowicz
Doris
D
Maio
Maurizio
M
Pittet
Pierre-André
PA
Golzio
Lucia
L
Giachetti
Claudio
C
Rocha
Cynthia
C
Bernardinelli
Gérald
G
Filinchuk
Yaroslav
Y
Scheer
Alexander
A
Schwarz
Matthias K
MK
Chollet
André
A
D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D015195:Drug Design; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy*; D007211:Indoles / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013141:Spiro Compounds; C036293:prostaglandin D2 receptor