ABSTRACT
CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [(35)S]guanosine 5(')-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3-30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.
Subject(s)
Drug Inverse Agonism , Histamine H3 Antagonists/pharmacology , Piperidines/pharmacology , Pyrazines/pharmacology , Spiro Compounds/pharmacology , Wakefulness/drug effects , Administration, Oral , Animals , Biological Availability , Brain/drug effects , Brain/metabolism , Dogs , Drinking/drug effects , Drinking/physiology , Drug Evaluation, Preclinical , Histamine Agonists/pharmacology , Histamine H3 Antagonists/pharmacokinetics , Humans , Macaca fascicularis , Male , Methylhistamines/pharmacology , Motor Activity/drug effects , Motor Activity/physiology , Piperidines/pharmacokinetics , Pyrazines/pharmacokinetics , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Sleep/drug effects , Sleep/physiology , Spiro Compounds/pharmacokinetics , Wakefulness/physiologyABSTRACT
In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually.
Subject(s)
Benzhydryl Compounds/chemistry , Central Nervous System Stimulants/chemistry , Sulfoxides/chemistry , Thiophenes/chemistry , Animals , Area Under Curve , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/pharmacokinetics , Central Nervous System Stimulants/chemical synthesis , Central Nervous System Stimulants/pharmacokinetics , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Half-Life , Modafinil , Protein Binding , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfoxides/chemical synthesis , Sulfoxides/pharmacokinetics , Symporters/chemistry , Symporters/metabolism , Thiophenes/chemical synthesis , Thiophenes/pharmacokinetics , Wakefulness/drug effectsABSTRACT
Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors).
Subject(s)
Benzhydryl Compounds/chemistry , Pyrrolidines/chemistry , Receptors, Histamine H3/chemistry , Sulfones/chemistry , Administration, Oral , Animals , Benzhydryl Compounds/agonists , Benzhydryl Compounds/pharmacokinetics , Central Nervous System Stimulants/agonists , Central Nervous System Stimulants/chemistry , Central Nervous System Stimulants/pharmacokinetics , Drug Inverse Agonism , Half-Life , Kinetics , Modafinil , Protein Binding , Pyrrolidines/agonists , Pyrrolidines/pharmacokinetics , Rats , Receptors, Histamine H3/metabolism , Structure-Activity Relationship , Sulfones/agonists , Sulfones/pharmacokinetics , Wakefulness/drug effectsABSTRACT
In search of a next generation molecule to the novel wake promoting agent modafinil, a series of diphenyl ether derived wakefulness enhancing agents (in rat) was developed. From this work, racemic compound 16 was separated into its chiral enantiomers to profile them individually.
Subject(s)
Benzhydryl Compounds/pharmacology , Wakefulness/drug effects , Animals , Benzhydryl Compounds/chemistry , Cytochrome P-450 Enzyme Inhibitors , Drug Discovery , Humans , Modafinil , RatsABSTRACT
In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3).
Subject(s)
Benzhydryl Compounds/chemistry , Fluorenes/chemistry , Neuroprotective Agents/chemistry , Sulfoxides/chemistry , Animals , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/pharmacokinetics , Brain/drug effects , Brain/metabolism , Fluorenes/chemical synthesis , Fluorenes/pharmacokinetics , Injections, Intraperitoneal , Modafinil , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacokinetics , Rats , Sulfoxides/chemical synthesis , Sulfoxides/pharmacokineticsABSTRACT
Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.
Subject(s)
Drug Inverse Agonism , Histamine Agonists , Ketones/chemistry , Wakefulness/drug effects , 1-Propanol/chemistry , 1-Propanol/pharmacology , Animals , Histamine Agonists/chemistry , Histamine Agonists/pharmacology , Humans , Ketones/pharmacology , Methylamines/chemistry , Methylamines/pharmacology , Phenols/chemistry , Phenols/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Sleep Disorders, Circadian Rhythm/drug therapyABSTRACT
In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously disclosed bi-phenyl derived racemate compound (±)-2 as a new generation of wake-promoting agent. Here we describe the profiles of the individual enantiomers (-)-2 and (+)-2, respectively.
Subject(s)
Biphenyl Compounds/chemical synthesis , Central Nervous System Stimulants/chemical synthesis , Wakefulness/drug effects , Animals , Area Under Curve , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Central Nervous System Stimulants/pharmacokinetics , Central Nervous System Stimulants/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Electroencephalography , Injections, Intraperitoneal , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Retinoic Acid 4-Hydroxylase , Sleep/drug effects , Stereoisomerism , Structure-Activity Relationship , Wakefulness/physiologyABSTRACT
Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.
Subject(s)
Histamine Agonists/pharmacology , Ketones/chemistry , Morpholines/chemistry , Receptors, Histamine H3 , Wakefulness/drug effects , Animals , Electroencephalography , Histamine Agonists/chemistry , Humans , Ketones/pharmacology , Male , Molecular Structure , Morpholines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited â¼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test.
Subject(s)
Brain/drug effects , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , Animals , Dogs , Humans , Inhibitory Concentration 50 , Mice , Microsomes, Liver/drug effects , Molecular Structure , Rats , Receptors, Serotonin , Serotonin Antagonists/pharmacokinetics , StereoisomerismABSTRACT
In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.
Subject(s)
Benzhydryl Compounds/chemical synthesis , Biphenyl Compounds/chemical synthesis , Central Nervous System Stimulants/chemical synthesis , Wakefulness/drug effects , Animals , Area Under Curve , Benzhydryl Compounds/pharmacokinetics , Benzhydryl Compounds/pharmacology , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Central Nervous System Stimulants/pharmacokinetics , Central Nervous System Stimulants/pharmacology , Electroencephalography , Injections, Intraperitoneal , Male , Modafinil , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Sleep/drug effects , Stereoisomerism , Structure-Activity Relationship , Wakefulness/physiologyABSTRACT
CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3 receptor (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H3R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [³5S]guanosine 5'-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50 = 0.1 ± 0.003 mg/kg), and antagonism of the H3R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.
Subject(s)
Cognition/drug effects , Histamine H3 Antagonists/pharmacology , Nootropic Agents , Pyridazines/pharmacology , Pyrrolidines/pharmacology , Wakefulness/drug effects , Animals , Autoradiography , Behavior, Animal/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Dose-Response Relationship, Drug , Drinking/drug effects , Electroencephalography/drug effects , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Male , Memory, Short-Term/drug effects , Radioligand Assay , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Recognition, Psychology/drug effects , Reflex, Startle/drug effects , Sleep/drug effects , Social BehaviorABSTRACT
7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.
Subject(s)
Benzofurans/chemistry , Piperidines/chemistry , Receptors, Serotonin/chemistry , Serotonin Antagonists/pharmacology , Animals , Brain/embryology , Brain/metabolism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Kinetics , Memory, Short-Term/drug effects , Models, Chemical , Rats , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Carbazoles/chemical synthesis , Indazoles/chemical synthesis , Receptor, TIE-2/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Biological Availability , Carbazoles/pharmacokinetics , Carbazoles/pharmacology , Humans , Indazoles/pharmacokinetics , Indazoles/pharmacology , Macaca fascicularis , Male , Mice , Mice, Nude , Models, Molecular , Neovascularization, Physiologic/drug effects , Rats , Rats, Sprague-Dawley , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, TIE-2/chemistry , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/chemistry , Vascular Endothelial Growth Factor Receptor-3/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
Pyridazinone 1 was recently reported as a potent H(3)R antagonist with good drug-like properties and in vivo activity. A series of constrained amine analogs of 1 was synthesized to identify compounds with improved pharmacokinetic profiles. From these efforts, a new class of (S)-2-pyrrolidin-1-ylmethyl-1-pyrrolidinyl amides was identified.
Subject(s)
Amines/chemistry , Histamine H3 Antagonists/pharmacology , Pyridazines/pharmacology , Animals , Dose-Response Relationship, Drug , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/chemistry , Humans , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Rats , Receptors, Histamine H3/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.
Subject(s)
Drinking/drug effects , Histamine Agonists/pharmacology , Pyridazines/pharmacology , Wakefulness/drug effects , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Histamine Agonists/chemical synthesis , Histamine Agonists/chemistry , Humans , Male , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Rats , Receptors, Histamine H3/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Optimization of a novel series of pyridazin-3-one histamine H(3) receptor (H(3)R) antagonists/inverse agonists identified 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (8a, CEP-26401; irdabisant) as a lead candidate for potential use in the treatment of attentional and cognitive disorders. 8a had high affinity for both human (K(i) = 2.0 nM) and rat (K(i) = 7.2 nM) H(3)Rs with greater than 1000-fold selectivity over the hH(1)R, hH(2)R, and hH(4)R histamine receptor subtypes and against an in vitro panel of 418 G-protein-coupled receptors, ion channels, transporters, and enzymes. 8a demonstrated ideal pharmaceutical properties for a CNS drug in regard to water solubility, permeability and lipophilicity and had low binding to human plasma proteins. It weakly inhibited recombinant cytochrome P450 isoforms and human ether-a-go-go-related gene. 8a metabolism was minimal in rat, mouse, dog, and human liver microsomes, and it had good interspecies pharmacokinetic properties. 8a dose-dependently inhibited H(3)R agonist-induced dipsogenia in the rat (ED(50) = 0.06 mg/kg po). On the basis of its pharmacological, pharmaceutical, and safety profiles, 8a was selected for preclinical development. The clinical portions of the single and multiple ascending dose studies assessing safety and pharmacokinetics have been completed allowing for the initiation of a phase IIa for proof of concept.
Subject(s)
Histamine Antagonists/chemical synthesis , Pyridazines/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Histamine H3/metabolism , Animals , Biological Availability , Brain/metabolism , Crystallography, X-Ray , Dogs , Drug Inverse Agonism , Histamine Antagonists/pharmacology , Histamine Antagonists/toxicity , Humans , In Vitro Techniques , Macaca fascicularis , Male , Mice , Microsomes, Liver/metabolism , Permeability , Pyridazines/pharmacology , Pyridazines/toxicity , Pyrrolidines/pharmacology , Pyrrolidines/toxicity , Rats , Rats, Sprague-Dawley , Solubility , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity.
Subject(s)
Drug Design , Melanoma, Experimental/drug therapy , Oximes/chemical synthesis , Oximes/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Receptor, TIE-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Cell Proliferation/drug effects , Cells, Cultured , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Hemangiosarcoma/blood supply , Hemangiosarcoma/drug therapy , Hemangiosarcoma/enzymology , Humans , Melanoma, Experimental/blood , Melanoma, Experimental/blood supply , Melanoma, Experimental/enzymology , Molecular Structure , Neovascularization, Pathologic , Oximes/pharmacokinetics , Protein Kinase Inhibitors/pharmacokinetics , Rats , Receptor, TIE-2/metabolism , Structure-Activity Relationship , Umbilical Veins , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
KDR kinase inhibition is considered to play an important role in regulating angiogenesis, which is vital for the survival and proliferation of tumor cells. Recently we disclosed a structure-based kinase inhibitor design strategy which led to the identification of a new class of VEGFR-2/KDR kinase inhibitors bearing heterocyclic substituted pyrazolones as the core template. Instability in a rat S9 preparation and poor iv PK profiles for most of these inhibitors necessitated exploration of new pyrazolones to identify new analogs with improved metabolic stability. Optimization of the heterocyclic moiety led to the identification of the thiadiazole series of pyrazolones (D) as potent VEGFR-2/KDR kinase inhibitors. SAR modifications, kinase selectivity profiling, and structural elements for improved PK properties were explored. Oral bioavailability up to 29% was achieved in the rat. Modeling results based on the Glide XP docking approach supported our postulation regarding the interaction of the lactam segment of the pyrazolones with the hinge region of the KDR kinase.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrazolones/chemical synthesis , Pyrazolones/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Autoradiography , Biological Availability , Blotting, Western , Drug Design , Enzyme Inhibitors/pharmacokinetics , Humans , In Vitro Techniques , Models, Molecular , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrazolones/pharmacokinetics , Rats , Recombinant Proteins , Spectrometry, Fluorescence , Structure-Activity RelationshipABSTRACT
Structural analysis of the essential binding elements of the oxindole-based kinase inhibitor (1) led to the identification of a novel class of heterocyclic-substituted pyrazolones. Knoevenagel condensation of a variety of activated methylene nucleophiles with indole or pyrrole carboxaldehydes provided a focused library of molecules, each containing elements of kinase pharmacophore probe. Initial screening for VEGFR-2 kinase inhibition eliminated several of the probes. Identification of an active pyrazolone motif and further optimization resulted in several highly potent VEGFR-2 inhibitors with cellular efficacy, anti-angiogenic activity ex vivo in rat aortic ring explant cultures, and oral anti-tumor efficacy in nude mice.