Exploration of SAR features by modifications of thiazoleacetic acids as CRTH2 antagonists.
The SAR features have been further explored for (2-benzhydryl-4-phenyl-thiazol-5-yl)acetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. The introduction of a nitrogen or a methyl substituent in the benzhydrylic position offer two alternative drugable scaffolds attractive for unsymmetrically substituted derivatives. An imidazole analogue lacks activity due to formation of a favored coplanar intramolecular hydrogen bond. The pyrimidine derivative 18 represents a potent and selective compound that will be subject to continued investigations.
7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
Marie
M
Grimstrup
Jean-Marie
JM
Receveur
Øystein
Ø
Rist
Thomas M
TM
Frimurer
Peter Aadal
PA
Nielsen
Jesper M
JM
Mathiesen
Thomas
T
Högberg
D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D001559:Benzhydryl Compounds; D007093:Imidazoles; D011743:Pyrimidines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013844:Thiazoles; C029899:imidazole; C030986:pyrimidine; D009584:Nitrogen; C036293:prostaglandin D2 receptor