ABSTRACT
The objectives of the study were to characterize the selectivity of dantrolene to breast cancer resistance protein (Bcrp) and to evaluate whether cerebrospinal fluid (CSF) can be used as a surrogate to assess brain exposures of BCRP and P-glycoprotein (Pgp) substrates. The impact of Bcrp and Pgp on dantrolene exposures in brain and CSF was examined in Bcrp and Mdr1a/1b knockout mice and was further investigated in wild-type mice in the presence of the Bcrp inhibitor (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester (Ko143), the Pgp inhibitor 6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-l-valine-cyclosporine A (PSC833), and the dual inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). The effect of Bcrp and Pgp on digoxin exposures in brain and CSF was investigated in wild-type mice in the presence of the inhibitors. In vivo studies showed dantrolene exposures in brain and CSF, but not the blood, increased in Bcrp(-/-) and Mdr1a/1b(-/-)/Bcrp(-/-) mice, or in the presence of the Bcrp inhibitors Ko143 or GF120918. Inhibition of Pgp by GF120918 and PSC833 significantly increased digoxin exposures in brain, CSF, and blood to a lesser extent. Results from the present study demonstrated that inhibition of Bcrp and Pgp increased not only the exposures of dantrolene and digoxin in brain, but also the exposures in CSF. In addition, the change of exposures in CSF reflected the changes in brain. The present study strongly suggests that the dantrolene and digoxin exposures in CSF are primarily determined by the rapid transport from brain to CSF, and inhibition of Bcrp and Pgp exhibits little impact on using CSF as surrogates to assess brain exposures of Bcrp and Pgp substrates.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/metabolism , Blood-Brain Barrier/metabolism , Pharmaceutical Preparations , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/genetics , Animals , Biological Transport , Blood-Brain Barrier/drug effects , Caco-2 Cells , Dantrolene/administration & dosage , Dantrolene/blood , Dantrolene/cerebrospinal fluid , Digoxin/administration & dosage , Digoxin/blood , Digoxin/cerebrospinal fluid , Dose-Response Relationship, Drug , Humans , Mice , Mice, Knockout , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/blood , Pharmaceutical Preparations/cerebrospinal fluid , Time Factors , Tissue DistributionABSTRACT
Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (-)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability.
Subject(s)
Immunosuppressive Agents/pharmacology , Prodrugs/pharmacology , Receptors, Lysosphingolipid/agonists , Receptors, Lysosphingolipid/metabolism , Tetrahydronaphthalenes/pharmacology , Administration, Oral , Animals , Crystallography, X-Ray , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/metabolism , Immunosuppressive Agents/pharmacokinetics , Lymphopenia/chemically induced , Mice , Models, Molecular , Multiple Sclerosis/drug therapy , Phosphorylation , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Prodrugs/chemistry , Prodrugs/metabolism , Prodrugs/pharmacokinetics , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/metabolism , Tetrahydronaphthalenes/pharmacokineticsABSTRACT
The 4-(5-fluoro-6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl-1H-imidazol-2-ylamine 3 is a potent and selective inhibitor of TGF-betaR1. Substitution of the amino group of 3 typically led to a slight decrease in the affinity for the receptor and in TGF-beta-inducted PAI-luciferase reporter activity. However, 2-acetamidoimidazoles were identified as attractive candidates for further optimization as a result of their significant activity combined to their superior pharmacokinetic profile.
Subject(s)
Chemistry, Pharmaceutical/methods , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Animals , Catalytic Domain , Cell Line, Tumor , Drug Design , Humans , Inhibitory Concentration 50 , Luciferases/metabolism , Male , Models, Biological , Molecular Conformation , Rats , Rats, Sprague-DawleyABSTRACT
Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been demonstrated to be potent and selective adenosine A(2a) receptor antagonists with oral activity in rodent models of Parkinson's disease. We have replaced the piperazinyl group with a variety of linear, monocyclic, and bicyclic diamines. Of these diamines, (R)-2-(aminomethyl)pyrrolidine is a particularly potent and selective replacement for the piperazinyl group. With this diamine component, we have been able to prepare numerous analogues with low nanomolar affinity toward the A(2a) receptor and good selectivity with respect to the A(1) receptor (>200-fold in some cases). Selected analogues from this series of [1,2,4]triazolo[1,5-a][1,3,5]triazine have now been shown to be orally active in the mouse catalepsy model.
Subject(s)
Adenosine A2 Receptor Antagonists , Antiparkinson Agents/chemical synthesis , Diamines/chemical synthesis , Pyrrolidines/chemical synthesis , Triazines/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Antiparkinson Agents/chemistry , Antiparkinson Agents/pharmacology , Binding, Competitive , Biological Availability , Catalepsy/drug therapy , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Combinatorial Chemistry Techniques , Diamines/chemistry , Diamines/pharmacology , In Vitro Techniques , Male , Mice , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Stereoisomerism , Triazines/chemistry , Triazines/pharmacology , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
The [1,2,4]triazolo[1,5-a]triazine derivative 3, more commonly known in the field of adenosine research as ZM-241385, has previously been demonstrated to be a potent and selective adenosine A2a receptor antagonist, although with limited oral bioavailability. This [1,2,4]triazolo[1,5-a]triazine core structure has now been improved by incorporating various piperazine derivatives. With some preliminary optimization, the A2a binding affinity of some of the best piperazine derivatives is almost as good as that of compound 3. The selectivity level over the adenosine A1 receptor subtype for some of the more active analogues is also fairly high, > 400-fold in some cases. Many compounds within this piperazine series of [1,2,4]triazolo[1,5-a]triazine have now been shown to have good oral bioavailability in the rat, with some as high as 89% (compound 35). More significantly, some piperazines derivatives of [1,2,4]triazolo[1,5-a]triazine also possessed good oral efficacy in rodent models of Parkinson's disease. For instance, compound 34 was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopamine-lesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po.
