title: 4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists.
abstract: 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.
authors.affiliation: Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. adrian.cheung@roche.com
authors.forename: Adrian Wai-Hing
authors.initials: AW
authors.lastname: Cheung
authors.forename: John
authors.initials: J
authors.lastname: Brinkman
authors.forename: Fariborz
authors.initials: F
authors.lastname: Firooznia
authors.forename: Alexander
authors.initials: A
authors.lastname: Flohr
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Gubler
authors.forename: Kevin
authors.initials: K
authors.lastname: Guertin
authors.forename: Rachid
authors.initials: R
authors.lastname: Hamid
authors.forename: Nicholas
authors.initials: N
authors.lastname: Marcopulos
authors.forename: Roger D
authors.initials: RD
authors.lastname: Norcross
authors.forename: Lida
authors.initials: L
authors.lastname: Qi
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Ramsey
authors.forename: Jenny
authors.initials: J
authors.lastname: Tan
authors.forename: Yang
authors.initials: Y
authors.lastname: Wen
authors.forename: Ramakanth
authors.initials: R
authors.lastname: Sarabu
mesh_terms: 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*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D052160:Benzothiazoles; D043704:Receptor, Adenosine A2B; D019820:Xanthine