ABSTRACT
We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Animals , Humans , Mice , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Optimization of the ADME properties of a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase resulted in the identification of highly selective compounds with properties suitable for use as in vitro and in vivo tools to probe the effects of Sky inhibition.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Animals , Humans , Mice , Receptor Protein-Tyrosine Kinases/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.
Subject(s)
Chemistry, Pharmaceutical/methods , Intestines/drug effects , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Absorption , Adenosine Triphosphate/chemistry , Administration, Oral , Animals , Binding Sites , Biological Availability , Crystallography, X-Ray/methods , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Platelet Aggregation , Rats , Receptor Protein-Tyrosine Kinases/chemistryABSTRACT
The P2Y(1) and P2Y(12) purinergic receptors are responsible for mediating adenosine diphosphate (ADP) dependent platelet aggregation. Evidence from P2Y(1) knockout studies as well as from nucleotide-based small molecule P2Y(1) antagonists has suggested that the antagonism of this receptor may offer a novel and effective method for the treatment of thrombotic disorders. Herein, we report the identification and optimization of a series of non-nucleotide P2Y(1) antagonists that are potent and orally bioavailable.
