ABSTRACT
Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl glutamate pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized through modifications at the 4-position of the pyridine ring and the terminal nitrogen of the piperazine ring, leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavailability. Compound 47s was selected for further preclinical evaluations.
Subject(s)
Piperazines/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Purinergic P2 Receptor Antagonists , Pyridines/pharmacokinetics , Administration, Oral , Adolescent , Adult , Aged , Animals , Biological Availability , CHO Cells , Cricetinae , Cricetulus , Female , Glutamates/chemical synthesis , Glutamates/pharmacokinetics , Humans , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Middle Aged , Piperazines/chemical synthesis , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Rats , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2Y12 , Structure-Activity Relationship , Young AdultABSTRACT
Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.
Subject(s)
Fibrinolytic Agents/pharmacology , Glutamic Acid/chemical synthesis , Piperidines/chemical synthesis , Platelet Aggregation/drug effects , Purinergic P2 Receptor Antagonists , Pyridines/chemical synthesis , Pyridines/pharmacology , Administration, Oral , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/chemistry , Glutamic Acid/chemistry , Glutamic Acid/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Pyridines/chemistry , Rats , Receptors, Purinergic P2Y12 , Structure-Activity RelationshipABSTRACT
Piperazinyl-glutamate-pyrimidines were prepared with oxygen, nitrogen, and sulfur substitution at the 4-position of the pyrimidine leading to highly potent P2Y12 antagonists. In particular, 4-substituted piperidine-4-pyrimidines provided compounds with exceptional potency. Pharmacokinetic and physicochemical properties were fine-tuned through modifications at the 4-position of the piperidine ring leading to compounds with good human PRP potency, selectivity, clearance and oral bioavailability.
Subject(s)
Fibrinolytic Agents/chemistry , Glutamic Acid/chemistry , Piperidines/chemistry , Platelet Aggregation/drug effects , Purinergic P2 Receptor Antagonists , Pyrimidines/chemistry , Animals , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/pharmacokinetics , Humans , Male , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2Y12 , Structure-Activity RelationshipABSTRACT
Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 22J with good human PRP potency, selectivity, in vivo efficacy and oral bioavailability.