4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists.
7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.
Cheung
Adrian Wai-Hing
AW
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. adrian.cheung@roche.com
Brinkman
John
J
Firooznia
Fariborz
F
Flohr
Alexander
A
Grimsby
Joseph
J
Gubler
Mary Lou
ML
Guertin
Kevin
K
Hamid
Rachid
R
Marcopulos
Nicholas
N
Norcross
Roger D
RD
Qi
Lida
L
Ramsey
Gwendolyn
G
Tan
Jenny
J
Wen
Yang
Y
Sarabu
Ramakanth
R
D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D013329:Structure-Activity Relationship; D019820:Xanthine / Q000737:chemistry*
D058917:Adenosine A2 Receptor Antagonists; D052160:Benzothiazoles; D043704:Receptor, Adenosine A2B; D019820:Xanthine