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
The work described herein demonstrates the utility of structure-based drug design (SBDD) in shifting the binding mode of an HTS hit from a DFG-in to a DFG-out binding mode resulting in a class of novel potent CSF-1R kinase inhibitors suitable for lead development.
Subject(s)
Protein Kinase Inhibitors/chemistry , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Binding Sites , Crystallography, X-Ray , Drug Design , High-Throughput Screening Assays , Hydrogen Bonding , Molecular Conformation , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/metabolismABSTRACT
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.
Subject(s)
Glutamic Acid/chemistry , Piperazines/chemistry , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation/drug effects , Purinergic P2 Receptor Antagonists , Pyridines/chemistry , Administration, Oral , Animals , Biological Availability , Humans , Male , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2Y12 , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-1-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate (TC) in H14 cells. A 3R,4R,5R/3S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Benzothiepins/chemical synthesis , Bile Acids and Salts/metabolism , Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors , Symporters/antagonists & inhibitors , Animals , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Benzothiepins/chemistry , Benzothiepins/pharmacology , Biological Availability , Cell Line , Cricetinae , Crystallography, X-Ray , Humans , Magnetic Resonance Spectroscopy , Male , Mesocricetus , Rats , Stereoisomerism , Structure-Activity Relationship , Taurocholic Acid/metabolismABSTRACT
In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Benzothiepins/chemical synthesis , Bile Acids and Salts/metabolism , Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors , Symporters/antagonists & inhibitors , Absorption , Animals , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacokinetics , Benzothiepins/chemistry , Benzothiepins/pharmacokinetics , Cell Line , Cricetinae , Crystallization , Humans , Humidity , Male , Mesocricetus , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity Relationship , Taurocholic Acid/metabolism , X-Ray DiffractionABSTRACT
A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead 22, various structural features were explored with respect to inhibition of the CETP-mediated transfer of [(3)H]cholesterol from high-density cholesterol donor particles to low-density cholesterol acceptor particles. The free hydroxyl group of the propanol was required for high potency, since acylation or alkylation reduced activity. High inhibitory potency was also associated with 3-ether moieties in the aniline ring, and the highest potencies were exhibited by 3-phenoxyaniline analogues. Activity was substantially reduced by oxidation or substitution in the methylene of the benzylic group, implying that the benzyl ring orientation was important for activity. In the benzylic group, substitution at the 3-position was preferred over either the 2- or the 4-positions. Highest potencies were observed with inhibitors in which the 3-benzylic substituent had the potential to adopt an out of plane orientation with respect to the phenyl ring. The best 3-benzylic substituents were OCF(2)CF(2)H (42, IC(50) 0.14 microM in buffer, 5.6 microM in human serum), cyclopentyl (39), 3-iso-propoxy (27), SCF(3) (67), and C(CF(3))(2)OH (36). Separation of 42 into its enantiomers unexpectedly showed that the minor R(+) enantiomer 1a was 40-fold more potent (IC(50) 0.02 microM in buffer, 0.6 microM in human serum) than the major S(-) enantiomer 1b, demonstrating that the R-chirality at the propanol 2-position is key to high potency in this series. The R(+) enantiomer 1a represents the first reported acyclic CETP inhibitor with submicromolar potency in plasma. A chiral synthesis of 1a is reported.