ABSTRACT
The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A(2B) antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A(2A) and A(1) receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A(2A) and A(1) receptors.
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Benzothiazoles/pharmacology , Drug Discovery , Benzothiazoles/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Benzothiazoles/pharmacology , Receptor, Adenosine A2B/metabolism , Xanthine/chemistry , Adenosine A2 Receptor Antagonists/chemistry , Benzothiazoles/chemistry , Structure-Activity RelationshipABSTRACT
New modifications on the C-8 4-aminobenzyl unit of the previously reported 3-alkyl-1,8-dibenzylxanthine inhibitors of cPEPCK are presented. The most active compound reported here is the 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid amide derivative 2 with an IC(50) of 0.29+/-0.08 microM. An X-ray analysis of a heteroaromatic sulfonamide is presented showing a new pi-pi interaction.
Subject(s)
Cytosol/enzymology , Enzyme Inhibitors/pharmacology , Phosphoenolpyruvate Carboxykinase (GTP)/antagonists & inhibitors , Xanthines/pharmacology , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Xanthines/chemistryABSTRACT
The analysis of the X-ray structures of two xanthine inhibitors bound to PEPCK and a comparison to the X-ray structure of GTP bound to PEPCK are reported. The SAR at N-1, N-7 and developing SAR at C-8 are consistent with information gained from the X-ray structures of compounds 1 and 2 bound to PEPCK. Representative N-3 modifications of compound 2 that led to the discovery of 3-cyclopropylmethyl and its carboxy analogue as optimal N-3 groups are presented.
Subject(s)
Phosphoenolpyruvate Carboxykinase (ATP)/metabolism , Xanthines/chemical synthesis , Xanthines/pharmacology , Crystallography, X-Ray , Guanosine Triphosphate/metabolism , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Phosphoenolpyruvate Carboxykinase (ATP)/drug effects , Structure-Activity RelationshipABSTRACT
The first non-substrate like inhibitors of human cytosolic phosphoenolpyruvate carboxykinase (PEPCK) competitive with GTP are reported. An effort to discover orally active compounds that improve glucose homeostasis in Type 2 diabetics by reversibly inhibiting PEPCK led to the discovery of 1-allyl-3-butyl-8-methylxanthine (5). We now report modifications at N-1 and C-8 that improved the in vitro activity of the initial xanthine HTS hit by 100-fold and a developing SAR for this class of inhibitor.
