KDR Kinase Inhibitors Research Articles

Pharmacophore Modeling and in Silico Screening Studies to Design Potential KDR Kinase Inhibitors

A novel ligand-based pharmacophore model for KDR kinase was generated on the basis of chemical features of 30 KDR kinase inhibitors. This pharmacophore model consists of one hydrogen-bond acceptor, one hydrogen-bond donor and two hydrophobic groups. Several methods have been used to validate the model, suggesting that it can serve as a reliable tool for virtual screening to facilitate the discovery of novel KDR inhibitors. The model was then used as database search query from the National Cancer Institute (NCI) database for the rational design to identify new hit compound.

3D-QSAR Studies of Various Diaryl Urea Derivatives of Multi-targeted Receptor Tyrosine Kinase Inhibitors: Molecular Field Analysis Approach

3D-QSAR analysis has been performed on a series of diaryl urea derivatives of multi-targeted receptor tyrosine kinase inhibitors. Models were developed using the most widely used computational approach molecular field analysis (MFA) from our dataset for the KDR, cKit and FLT3 inhibitors using genetic partial least square (G/PLS) method. These models showed excellent internal predictability and consistency and validation using test set compounds yielded a good predictive power for the activity values of three set of inhibitors. These models would offer utility in guiding the rational design of multi-targeted KDR, cKit and FLT3 receptor tyrosine kinase inhibitors for therapeutic applications. Keywords: QSAR, Receptor tyrosine kinase, MFA, Molecular field analysis, Genetic partial least squares (G/PLS) method

Tandem C-N/Suzuki Coupling as the Key Step in the Syntheses of KDR Kinase Inhibitors

The Pd-catalyzed tandem C-N/Suzuki coupling reaction which offers an easy access to 2-substituted heteroaryl indoles is applied to the syntheses of biologically active KDR kinase inhibitors. The inhibitors can thus be synthesized in only five to seven steps with overall yields up to 63%.

1,4-Dihydroindeno[1,2-c]pyrazoles with Acetylenic Side Chains as Novel and Potent Multitargeted Receptor Tyrosine Kinase Inhibitors with Low Affinity for the hERG Ion Channel

The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.

Pharmacophore modeling and in silico screening for new KDR kinase inhibitors

In order to elucidate the essential structural features for KDR kinase inhibitors, three-dimensional pharmacophore hypotheses were built on the basis of a set of known KDR kinase inhibitors selected from the literature with CATALYST program. Several methods tools used in validation of pharmacophore hypothsis were presented, and the first hypothesis (Hypo1) was considered to be the best pharmacophore hypothesis. The model (Hypo1) was then employed as 3D search query to screen the Traditional Chinese Medicine Database (TCMD) for other potential lead compounds. One hit illustrated high binding affinity with KDR kinase measured by the surface plasmon resonance biosensor. Docking studies may help elucidate the mechanisms of KDR kinase receptor–ligand interactions.

Efficient Syntheses of KDR Kinase Inhibitors Using a Pd-Catalyzed Tandem C−N/Suzuki Coupling as the Key Step

A family of four potent KDR kinase inhibitors containing an indol-2-yl quinolin-2-one structure was utilizing a Pd-catalyzed tandem C-N and C-C coupling sequence.

1,2,3-Thiadiazole substituted pyrazolones as potent KDR/VEGFR-2 kinase inhibitors

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.

Hit‐to‐Lead Optimization of 1,4‐Dihydroindeno[1,2‐c]pyrazoles as a Novel Class of KDR Kinase Inhibitors.

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A General Approach to Indoles: Practical Applications for the Synthesis of Highly Functionalized Pharmacophores

The development of a long-term manufacturing route to a potent and selective KDR kinase inhibitor has led to the discovery of several novel methodologies for the general synthesis of indoles. The key transformations involved addition of a trimethylsilylnitro benzene to an aromatic aldehyde which afforded the key nitroalcohol intermediate. Oxidation of the nitroalcohol intermediate led to a nitroketone; whereas, elimination afforded exclusively a trans-nitrostyrene. Reductive cyclization gave the target compounds in excellent overall yield from readily available bulk chemicals. Application of this methodology has led to the synthesis of highly functionalized pharmacophores including other KDR kinase inhibitors, biindoles and tjipanazole natural products, indolo[2,3-a]pyrrolo [3,4-c]carbazoles, indole-4-carboxylic amides, N-hydroxyindoles, and 2,3-dihydrobenzofurans.

Scoring of KDR Kinase Inhibitors: Using Interaction Energy as a Guide for Ranking

Within a congeneric series of ATP-competitive KDR kinase inhibitors, we determined that the IC(50) values, which span four orders of magnitude, correlated best with the calculated ligand-protein interaction energy using the Merck Molecular Force Field (MMFFs(94)). Using the ligand-protein interaction energy as a guide, we outline a workflow to rank order virtual KDR kinase inhibitors prior to synthesis. When structural information of the target is available, the ability to score molecules a priori can be used to rationally select reagents. Our implementation allows one to select thousands of readily available reagents, enumerate compounds in multiple poses and score molecules in the active site of a protein within a few hours. In our experience, virtual library enumeration is best used when a correlation between computed descriptors/properties and IC(50) or K (i) values has been established.

Hit-to-lead optimization of 1,4-dihydroindeno[1,2- c]pyrazoles as a novel class of KDR kinase inhibitors

A series of 1,4-dihydroindeno[1,2- c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.

Potent N-(1,3-Thiazol-2-yl)pyridin-2-amine Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors with Excellent Pharmacokinetics and Low Affinity for the hERG Ion Channel

A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.

Synthesis of Novel KDR Kinase Inhibitors through Catalytic Reductive Cyclization of o-Nitrobenzylcarbonyl Compounds

An efficient synthesis of o-nitrobenzylcarbonyl compounds is demonstrated through the Swern-type oxidation of readily accessible phenethanol analogues. Reductive cyclization of o-nitrobenzylcarbonyl 3 using catalytic Raney nickel gives 1H-indol-2-yl-1H-quinoline 2 in 95% yield. Hydrolysis of 2 affords the KDR kinase inhibitor 1 in quantitative yield. The examination of the reductive cyclization reaction and optimization of conditions is described.

Isoindolinone ureas: a novel class of KDR kinase inhibitors

A series of substituted isoindolinone ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 14c, are potent inhibitors of KDR both enzymatically (<50 nM) and cellularly (⩽100 nM). A 3D KDR/CDK2/MAP kinase overlay model with several structurally related tyrosine kinase inhibitors was used to predict the binding interactions of the isoindolinone ureas with the KDR active site.

The discovery of N-(1,3-thiazol-2-yl)pyridin-2-amines as potent inhibitors of KDR kinase

An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.

Optimization of the Indolyl Quinolinone Class of KDR (VEGFR‐2) Kinase Inhibitors: Effects of 5‐Amido‐ and 5‐Sulfonamido‐indolyl Groups on Pharmacokinetics and hERG Binding.

Optimization of the Indolyl Quinolinone Class of KDR (VEGFR‐2) Kinase Inhibitors: Effects of 5‐Amido‐ and 5‐Sulfonamido‐indolyl Groups on Pharmacokinetics and hERG Binding.

Property-Based Design of KDR Kinase Inhibitors

Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.

Rapid and Efficient Synthesis of 1H‐Indol‐2‐yl‐1H‐quinolin‐2‐ones.

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Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF-receptor KDR

3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class of KDR kinase inhibitors. A variety of imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were identified with good aqueous solubility.

Optimization of the indolyl quinolinone class of KDR (VEGFR-2) kinase inhibitors: effects of 5-amido- and 5-sulphonamido-indolyl groups on pharmacokinetics and hERG binding

Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I Kr potassium channel hERG. ©2003 Elsevier Science Ltd. All rights reserved.