Diazine indole acetic acids as potent, selective, and orally bioavailable antagonists of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) for the treatment of allergic inflammatory diseases.
New classes of CRTH2 antagonists, the pyridazine linker containing indole acetic acids, are described. The initial hit 1 had good potency but poor permeability, metabolic stability, and PK. Initial optimization led to compounds of type 2 with low oxidative metabolism but poor oral bioavailability. Poor permeability was identified as a liability for these compounds. Addition of a linker between the indole and diazine moieties afforded a series with good potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. 32 was identified as the development track candidate. It was potent in cell based, binding, and whole blood assays and exhibited good PK profile. It was efficacious in mouse models of contact hypersensitivity (1 mg/kg b.i.d.) and house dust (20 mg/kg q.d.) when dosed orally. In sheep asthma, administration at 1 mg/kg iv completely blocked the LAR and AHR and attenuated the EAR phase.
BioTherapeutics Chemistry, Pfizer Worldwide Medicinal Chemistry, 200 Cambridgepark Drive, Cambridge, Massachusetts 02140, United States. neelu.kaila@pfizer.com
Neelu
N
Kaila
Adrian
A
Huang
Alessandro
A
Moretto
Bruce
B
Follows
Kristin
K
Janz
Michael
M
Lowe
Jennifer
J
Thomason
Tarek S
TS
Mansour
Cedric
C
Hubeau
Karen
K
Page
Paul
P
Morgan
Susan
S
Fish
Xin
X
Xu
Cara
C
Williams
Eddine
E
Saiah
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016084:Bronchoconstriction / Q000187:drug effects; D018938:Caco-2 Cells; D048430:Cell Shape / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000276:immunology; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000276:immunology; D007118:Immunoassay; D007210:Indoleacetic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D039981:Pyroglyphidae / Q000276:immunology; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D012756:Sheep; D013329:Structure-Activity Relationship
D007210:Indoleacetic Acids; D011724:Pyridazines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor