ABSTRACT
Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.
Subject(s)
Aza Compounds/pharmacology , Indazoles/pharmacology , Receptors, CCR1/antagonists & inhibitors , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Dose-Response Relationship, Drug , Drug Design , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Molecular Structure , Receptors, CCR1/metabolism , Structure-Activity RelationshipABSTRACT
A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.
Subject(s)
Amides/pharmacology , Drug Discovery , Pyrazoles/pharmacology , Receptors, CCR1/antagonists & inhibitors , Amides/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Pyrazoles/chemistry , Receptors, CCR1/metabolism , Structure-Activity RelationshipABSTRACT
Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.
Subject(s)
Benzamides/chemical synthesis , Guanidines/chemical synthesis , Myocardial Infarction/drug therapy , Myocardial Reperfusion Injury/prevention & control , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Animals , Benzamides/chemistry , Benzamides/pharmacology , Biological Availability , Blood Platelets/cytology , Blood Platelets/drug effects , Cell Line , Cell Membrane Permeability , Cell Size , Cytochrome P-450 Enzyme Inhibitors , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Guanidines/chemistry , Guanidines/pharmacology , Humans , Male , Membranes, Artificial , Microsomes, Liver/metabolism , Models, Molecular , Permeability , Protein Isoforms/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Sodium-Hydrogen Exchanger 1 , Structure-Activity RelationshipABSTRACT
A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were optimized for cellular potency and kinase selectivity. This led to the identification of compound 24, BIX 02565, an attractive candidate for use in vitro and in vivo to explore the role of RSK as a target for the treatment heart failure.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Amides/chemistry , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Drug Evaluation, Preclinical/methods , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Nitrogen/chemistry , Structure-Activity RelationshipABSTRACT
A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were identified through high throughput screening. An RSK crystal structure and exploratory SAR were used to define the series pharmacophore. Compounds with good cell potency, such as compounds 43, 44, and 55 were identified, and form the basis for subsequent kinase selectivity optimization.
Subject(s)
Azepines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Amides/chemistry , Azepines/pharmacology , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Nitrogen/chemistry , Structure-Activity RelationshipABSTRACT
A 270-membered library of trisubstituted ureas was synthesized and evaluated for inhibition of soluble epoxide hydrolase. Library design and reagent selection was guided by the use of a pharmacophore model and synthesis of the array was enabled with a general solid-phase method. This array approach facilitated multi-dimensional SAR around this series and identified functionality responsible for binding affinity, as well as opportunities for modulating the overall in vitro profiles of this class of soluble epoxide hydrolase inhibitors.
Subject(s)
Combinatorial Chemistry Techniques/methods , Enzyme Inhibitors/chemical synthesis , Epoxide Hydrolases/antagonists & inhibitors , Small Molecule Libraries/chemical synthesis , Urea/analogs & derivatives , Animals , Humans , Protein Binding , Solubility , Structure-Activity Relationship , Urea/chemistryABSTRACT
An effort aimed at exploring structural diversity in the N-pyrazole-N'-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N'-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-alpha production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency.
Subject(s)
2-Naphthylamine/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , Urea/analogs & derivatives , p38 Mitogen-Activated Protein Kinases/metabolism , 2-Naphthylamine/chemistry , Animals , Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Inhibitory Concentration 50 , Lipopolysaccharides/metabolism , Mice , Models, Chemical , Molecular Structure , Tumor Necrosis Factor-alpha/metabolism , Urea/chemistryABSTRACT
Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.
Subject(s)
Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Sulfonamides/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/chemistry , Animals , Binding Sites , Biological Availability , Computer Simulation , Crystallography, X-Ray , Drug Design , Lipopolysaccharides/pharmacology , Male , Mice , Niacinamide/analogs & derivatives , Niacinamide/chemical synthesis , Niacinamide/chemistry , Niacinamide/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Discovery of the pyrazole-naphthyl urea class of p38 MAP kinase inhibitors typified by the clinical candidate BIRB 796 has encouraged further exploration of this particular scaffold. Modification to the part of the inhibitor that occupies the adenine/ATP binding site has resulted in a new way to obtain potent inhibitors that possess favorable in vitro and in vivo properties.
Subject(s)
Adenine/metabolism , Protein Kinase Inhibitors/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Binding Sites , Humans , Models, Molecular , Protein Kinase Inhibitors/metabolism , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH(2) interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degrees C translating into K(d) values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Naphthalenes/chemical synthesis , Pyrazoles/chemical synthesis , Urea/analogs & derivatives , Urea/chemical synthesis , Animals , Cell Line , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme-Linked Immunosorbent Assay , Heating , Humans , In Vitro Techniques , Ligands , Lipopolysaccharides/pharmacology , Mice , Mitogen-Activated Protein Kinase 14 , Mitogen-Activated Protein Kinases/chemistry , Naphthalenes/chemistry , Protein Binding , Protein Denaturation , Pyrazoles/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesis , Urea/chemistryABSTRACT
BIRB 796, a member of the N-pyrazole-N'-naphthly urea class of p38MAPK inhibitors, binds to the kinase with both slow association and dissociation rates. Prior to binding, the kinase undergoes a reorganization of the activation loop exposing a critical binding domain. We demonstrate that, independent of the loop movement, association rates are governed by low energy conformations of the inhibitor and polar functionality on the tolyl ring. As anticipated, the dissociation rates of the inhibitors from the kinase are slowed by lipophilic and hydrogen bond interactions. The value of structure-kinetic relationships (SKR) in drug design is discussed.
Subject(s)
Enzyme Inhibitors/chemistry , Mitogen-Activated Protein Kinases/metabolism , Naphthalenes/chemistry , Pyrazoles/chemistry , Autoimmune Diseases/drug therapy , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Kinetics , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/chemistry , Naphthalenes/pharmacology , Protein Binding , Protein Structure, Tertiary , Pyrazoles/pharmacology , Structure-Activity Relationship , p38 Mitogen-Activated Protein KinasesABSTRACT
We report on a series of N-pyrazole, N'-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5'-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.
