ABSTRACT
A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood.
Subject(s)
Receptors, CCR2/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Administration, Oral , Animals , Gene Knock-In Techniques , Guanosine 5'-O-(3-Thiotriphosphate)/blood , Humans , Mice , Mice, Inbred C57BL , Protein Binding/drug effects , Rats , Receptors, CCR2/genetics , Receptors, CCR2/metabolism , Serum Albumin/metabolism , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.
Subject(s)
Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/enzymology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/chemistry , Pyrimidines/therapeutic use , rho-Associated Kinases/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Administration, Oral , Aldehydes/chemistry , Animals , Crystallography, X-Ray , Indazoles/chemistry , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Rats , Structure-Activity Relationship , rho-Associated Kinases/metabolismABSTRACT
Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension.
Subject(s)
Chemistry, Pharmaceutical/methods , Piperazines/pharmacology , Receptors, Opioid, kappa/antagonists & inhibitors , Taurine/analogs & derivatives , Urotensins/antagonists & inhibitors , Acamprosate , Animals , Aorta/metabolism , Drug Design , Humans , Hypertension/drug therapy , Models, Chemical , Piperazines/chemistry , Rats , Structure-Activity Relationship , Taurine/drug effectsABSTRACT
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
Subject(s)
Chemistry, Pharmaceutical/methods , Urotensins/antagonists & inhibitors , Administration, Oral , Animals , Brain/metabolism , Chromatography, High Pressure Liquid , Diamines/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Rats , Receptors, Opioid, kappa/chemistry , Stereoisomerism , Structure-Activity Relationship , Urotensins/chemistryABSTRACT
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
Subject(s)
Aniline Compounds/pharmacology , Piperidones/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Administration, Oral , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Animals , Biological Availability , Cell Line , Drug Evaluation, Preclinical , Humans , Molecular Structure , Molecular Weight , Piperidones/chemical synthesis , Piperidones/chemistry , Rats , Small Molecule Libraries , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
Subject(s)
Antihypertensive Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Aorta/drug effects , Aorta/physiology , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Blood Pressure/drug effects , In Vitro Techniques , Models, Molecular , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity Relationship , rho-Associated KinasesABSTRACT
Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.
