ABSTRACT
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
Subject(s)
Benzimidazoles/chemistry , Chemistry, Pharmaceutical/methods , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Benzimidazoles/chemical synthesis , Binding Sites , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Chemical , Protein Binding , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).
Subject(s)
Acetates/chemical synthesis , Integrin alpha4beta1/antagonists & inhibitors , Piperazines/chemical synthesis , Piperidines/chemical synthesis , Proline/analogs & derivatives , Acetates/pharmacokinetics , Acetates/pharmacology , Animals , Dogs , Magnetic Resonance Spectroscopy , Male , Piperazines/pharmacokinetics , Piperazines/pharmacology , Piperidines/pharmacokinetics , Piperidines/pharmacology , Proline/chemical synthesis , Proline/pharmacokinetics , Proline/pharmacology , Rats , Rats, Sprague-Dawley , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.
