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
[This corrects the article DOI: 10.1021/acsmedchemlett.8b00344.].
ABSTRACT
RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.
Subject(s)
Benzothiazoles/pharmacology , Phosphates/pharmacology , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors , Animals , Benzothiazoles/chemistry , Benzothiazoles/pharmacokinetics , Benzothiazoles/therapeutic use , Colitis/drug therapy , Dogs , Drug Discovery , Humans , Male , Mice , Molecular Docking Simulation , Phosphates/chemistry , Phosphates/pharmacokinetics , Phosphates/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Quinazolines/therapeutic use , Rats, Sprague-Dawley , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Swine , Swine, MiniatureABSTRACT
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
RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 µM).
ABSTRACT
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.
Subject(s)
Amides/chemical synthesis , Antihypertensive Agents/chemical synthesis , Indazoles/chemical synthesis , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridones/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Aorta/drug effects , Aorta/physiology , Blood Pressure/drug effects , In Vitro Techniques , Indazoles/pharmacokinetics , Indazoles/pharmacology , Intracellular Signaling Peptides and Proteins/chemistry , Models, Molecular , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Protein Serine-Threonine Kinases/chemistry , Pyridones/pharmacokinetics , Pyridones/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity Relationship , rho-Associated KinasesABSTRACT
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
In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties.
Subject(s)
Diamines/chemistry , Diamines/pharmacology , Factor Xa Inhibitors , Anticoagulants/chemistry , Anticoagulants/pharmacology , Binding Sites , Humans , Models, Molecular , Molecular Structure , Prothrombin Time , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
We previously reported a series of enantiopure cis-(1R,2S)-cyclopentyldiamine derivatives as potent and selective inhibitors of Factor Xa (FXa). Herein, we describe our approach to improve the metabolic stability of this series via core modifications. Multiple resulting series of compounds demonstrated similarly high FXa potency and improved metabolic stability in human liver microsomes compared with the cyclopentyldiamide 1. (3R,4S)-Pyrrolidinyldiamide 31 was the best overall compound with human FXa K(i) of 0.50 nM, PT EC(2x) of 2.1 microM in human plasma, bioavailability of 25% and t(1/2)of 2.7h in dogs. Further biochemical characterization of compound 31 is also presented.