2-Amino-5-benzoyl-4-phenylthiazoles: Development of potent and selective adenosine A1 receptor antagonists.
A series of 2-amino-5-benzoyl-4-phenylthiazole derivatives was investigated in radioligand binding studies at adenosine receptor (AdoR) subtypes with the goal to obtain potent and A(1)-selective antagonists. Acylation of the 2-amino group was found to be crucial for high A(1) affinity. The best compound of the present series was 2-benzoylamino-5-p-methylbenzoyl-4-phenylthiazole (16 m) showing a K(i) value of 4.83 nM at rat and 57.4 nM at human A(1) receptors combined with high selectivity versus the other AdoR subtypes. The compound behaved as an antagonist in GTP shift assays at A(1) receptors. Compound 16 m may serve as a new lead structure for the development of second-generation non-xanthine-derived A(1) antagonists which have potential as novel drugs.
Scheiff
Anja B
AB
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Yerande
Swapnil G
SG
Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Ahmedabad 380 054, Gujarat, India.
El-Tayeb
Ali
A
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Li
Wenjin
W
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Inamdar
Gajanan S
GS
Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Ahmedabad 380 054, Gujarat, India.
Vasu
Kamala K
KK
Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Ahmedabad 380 054, Gujarat, India.
Sudarsanam
Vasudevan
V
Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Ahmedabad 380 054, Gujarat, India.
Müller
Christa E
CE
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D013844:Thiazoles