ABSTRACT
In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model.
Subject(s)
Adenosine A2 Receptor Antagonists , Aminopyridines/chemistry , Chemistry, Pharmaceutical/methods , Pyrimidines/chemical synthesis , Drug Design , Haloperidol/chemistry , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Models, Chemical , Parkinson Disease/therapy , Protein Binding , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor, Adenosine A1/chemistry , Receptor, Adenosine A2A/chemistry , Solubility , Structure-Activity RelationshipABSTRACT
A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition.
Subject(s)
Chemistry, Pharmaceutical/methods , Cytochrome P-450 CYP3A/chemistry , Ions , Receptors, LHRH/antagonists & inhibitors , Uracil/analogs & derivatives , Drug Design , Gonadotropin-Releasing Hormone/chemistry , Humans , Kinetics , Models, Chemical , Molecular Structure , Peptides/chemistry , Stereoisomerism , Structure-Activity Relationship , Uracil/chemistryABSTRACT
Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Adenosine A2 Receptor Antagonists , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Acetamides/chemistry , Animals , Binding Sites , Cyclization , Drug Evaluation, Preclinical , Hepatocytes/drug effects , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Pyrimidines/chemistry , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.
Subject(s)
Acetamides/pharmacology , Adenosine A2 Receptor Antagonists , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Pyrimidines/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Adenosine A1 Receptor Antagonists , Animals , Drug Evaluation, Preclinical , Ether-A-Go-Go Potassium Channels/metabolism , Hepatocytes/drug effects , Humans , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Wistar , Species Specificity , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Antiparkinson Agents/chemical synthesis , Catalepsy/prevention & control , Parkinson Disease/physiopathology , Phenoxyacetates/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Antiparkinson Agents/pharmacology , Catalepsy/chemically induced , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2D6 Inhibitors , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Electrophysiology , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Haloperidol/toxicity , Humans , Molecular Structure , Phenoxyacetates/chemistry , Phenoxyacetates/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.
Subject(s)
Adenosine A2 Receptor Antagonists , DNA-Binding Proteins/antagonists & inhibitors , Pyrimidines/pharmacology , Trans-Activators/antagonists & inhibitors , Cell Line , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors , Drug Design , Humans , Kinetics , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Receptor, Adenosine A2A/metabolism , Structure-Activity Relationship , Transcriptional Regulator ERGABSTRACT
Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.
Subject(s)
Acetamides/chemical synthesis , Adenosine A2 Receptor Antagonists , Antiparkinson Agents/chemical synthesis , Pyrimidines/chemical synthesis , Acetamides/pharmacokinetics , Acetamides/pharmacology , Animals , Antiparkinson Agents/pharmacokinetics , Antiparkinson Agents/pharmacology , Catalepsy/chemically induced , Catalepsy/psychology , Cell Line , Cloning, Molecular , Cricetinae , Cricetulus , Haloperidol , Humans , In Vitro Techniques , Male , Microsomes, Liver/metabolism , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Radioligand Assay , Rats , Rats, Wistar , Reaction Time/drug effects , Receptor, Adenosine A2A/genetics , Solubility , Structure-Activity Relationship , WaterABSTRACT
The present article describes a selection of a new class of small molecule antagonists for the h-GnRH receptor, their preparation, and evaluation in vitro. Three computational methods were combined into a consensus score, to rank order virtual templates. The top 5% of templates were further evaluated in silico and assessed for novelty and synthetic accessibility. The tetrahydropyrido[4,3-d]pyrimidine-2,4-dione core was selected for synthesis and evaluated in vitro. Using an array approach for analog design and synthesis, we were able to drive the binding below 10nM for the h-GnRH receptor after two rounds of optimization.
