ABSTRACT
A new 1,4-dihydropyridine 5a, containing a cyano group at the C3 position, was recently reported to possess excellent mineralocorticoid receptor (MR) antagonist in vitro potency and no calcium channel-blocker (CCB) activity. In the present study, we report the structure-activity relationships of this novel series of cyano ester dihydropyridines that resulted in R6 substituted analogues with improved metabolic stability while maintaining excellent MR antagonist activity and selectivity against other nuclear receptors. Further structure optimization with the introduction of five-membered ring heterocycles at R6 resulted in compounds with excellent MR antagonist potency and a suitable pharmacokinetic profile. In vivo studies of a promising tool compound in the Dahl salt-sensitive rat model of hypertension showed similar blood pressure (BP) reduction as the steroidal MR antagonist eplerenone, providing proof-of-concept (POC) for a nonsteroidal, orally efficacious MR antagonist.
Subject(s)
Antihypertensive Agents/chemical synthesis , Mineralocorticoid Receptor Antagonists , Nitriles/chemical synthesis , Pyridines/chemical synthesis , Animals , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Male , Models, Molecular , Nitriles/pharmacokinetics , Nitriles/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Inbred Dahl , Rats, Sprague-Dawley , Stereoisomerism , 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 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
Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH2 into PGD2, a mediator thought to play a pivotal role in airway allergy and inflammatory processes. In this letter, we report the discovery of an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.
ABSTRACT
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.
