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We have discovered novel inhibitors of VEGFR-2 kinase with low nanomolar potency in both enzymatic and cell-based assays. Active series are heteroaryl-ketone compounds containing a central aromatic ring with either an indazolyl or indolyl keto group in the ortho orientation to the benzylic amine group (Fig. 1). The best compounds were demonstrated to be inactive against a small select panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase, a close family member. In addition, the lead candidate 8 displayed acceptable exposure levels when administered orally to mice.

Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure–activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC50 values in the single-digit micromolar to submicromolar range).

A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.

Substituted 3-amino-2-hydroxyamides and related hydroxyamides and acylhydrazines were identified as inhibitors of human methionine aminopeptidase-2 (MetAP2). Examination of substituents through parallel synthesis and iterative structure-based design allowed the identification of potent inhibitors with good selectivity against MetAP1. Diacylhydrazine 3t (A-357300) was identified as an analogue displaying inhibition of methionine processing and cellular proliferation in human microvascular endothelial cells (HMVEC).

3-D-Quantitative structure–activity relationships of N -(3-acyloxy-2-benzylpropyl)- N ′-dihydroxytetrahydro-benzazepine and tetrahydroisoquinoline and N -(3-acyloxy-2-benzylpropyl)- N ′-(4-hydroxy-3-methoxybenzyl) thiourea analogues as potent vanilloid receptor ligands were investigated using the CoMFA and the COMSIA methods. The best CoMFA model obtained in this study from 29 substituted thiourea analogues is a two-component model with the following statistics. R 2 (cv) =0.407 and RMSE (cv) =0.532 for the cross-validation, and R 2 =0.705 and RMSE=0.375 for the fitted. The best COMSIA model obtained from the same 29 compounds is a two-component model with the following statistics: R 2 (cv) =0.336 and RMSE (cv) =0.563 for the cross-validation, and R 2 =0.693 and RMSE=0.382 for the fitted.

A series of indole containing oxazolines has been discovered as a result of structural modifications of the lead compound A-105972. The compounds exert their anticancer activity through inhibition of tubulin polymerization by binding at the colchicine site. A-289099 was identified as an orally active antimitotic agent active against various cancer cell lines including those that express the MDR phenotype. The anticancer activity, pharmacokinetics, and an efficient and enantioselective synthesis of A-289099 are described.

Thermodynamic quantitative structure–activity relationships (QSAR) for chymotrypsin–ligand binding is developed, and the results are compared for the effects of organic solvent on the substrate specificity of the enzymes to those in aqueous phosphate buffer. This is the first of such analysis utilizing thermodynamic QSAR. A possible explanation for the difference describing the effects of organic solvent for the binding of substituted phenyl esters of N -benzoyl l -alanine analogues [PhCONHCH(Me)COOC 6 H 4 -p-X, I ] observed in both the classical and the thermodynamic QSAR is presented.

3D-Quantitative structure-activity relationships of 2,4,5- and 2,3,4,5-substituted imidazoles as a novel class of potent and nontoxic modulators of Pgp mediated MDR were investigated using CoMFA and COMSIA approaches. The best CoMFA model obtained from 46 imidazole analogues is a two-component model with the following statistics. R(2)(cv)=0.643, RMSE(cv)=0.360 for the cross-validation, and R(2)=0.767, RMSE=0.290 for the fitted. The best COMSIA model obtained is also a two-component model with the following statistics. R(2)(cv)=0.619, RMSE(cv)=0.372 for the cross-validation, and R(2)=0.765, RMSE=0.292 for the fitted.

A protein contains a large amount of water molecules, and the nature of the interactions of the water molecules with a protein play an important role in the thermodynamics of the ligand binding process. In this paper, thermodynamic aspects of drug-receptor interactions, enthalpy-entropy compensation or reinforcement, hydrophobicity, and biological 2D- and 3D-QSAR are discussed. Comparisons of the thermodynamic QSAR of phenyl esters of N-benzoyl L-alanine in phosphate buffer and pentanol provide useful insight for the ligand-enzyme interactions.

Several 1,2,3,4-tetrahydro- and 7-N-hydroxycarbamate derivatives of the natural product rapamycin were prepared and assayed for their immunosuppressive and antifungal profiles. Substitutions at the 7-position indicate the possibility of a differentiated immunosuppressive to antifungal profile, whereas 40-position variants of the tetrahydro-analogues did not show similar differentiated activity.

Quantitative structure-activity relationships of 34 pyrrolidine-modified nicotine agonists are investigated for their binding affinity toward neuronal nicotinic acetylcholine receptor. The results indicate that a large substituent at the R1, R2, and R3 position is detrimental to the binding affinity. Likewise, a large substituent at the R2 alpha or R3 alpha position as well as a hydrogen bond accepting substituent at the R2 beta position are not beneficial to the binding.

We examined the ability of the comparative molecular field analysis (CoMFA) method to reproduce Hammett σ constants. The dataset includes 49 substituted benzoic acids. Molecular fields calculated with an H + probe and AM1 partial atomic charges produce a good fit and cross-validated estimate of σ. This estimate is more accurate than that found from a CoMFA analysis using charges based on fits to STO-3G electrostatic potential surfaces. It is also superior to that derived from regression analysis of the charges on the atoms. The relationships predicted the σ of 21 of 23 additional compounds to within 0.27 kcal/mol. We concluded that the CoMFA treatment of electrostatic effects is suitable for the examination of 3D quantitative structure-bioactivity relationships

Pyrimido-oxazepine based sub-micromolar inhibitors (2–4) for Aurora and FLT-3 were designed and synthesized. These preliminary results supported the potential use of pyrimido-oxazepines as a versatile template for developing specific kinase inhibitors.

A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.

The logarithm of capacity factors (log k ′) previously measured from the reversed-phase high-performance liquid chromatography (RP-HPLC) and the octanol-water partition coefficients (log P ) of a mixed set of substituted benzene, furan, benzofuran, pyrrole, 1-Me-pyrrole, indole, and N -methyl indole derivatives are correlated with the descriptors obtained from their three-dimensional structures using the comparative molecular field analysis (CoMFA) approach. The results provide an example where log k ′ and log P values are calculated directly from the three-dimensional structures for a mixed set of compounds.

Le compose du titre est obtenu via un C-12 O-carbamate (issu lui-meme de l'acylation d'un alcool allylique derive de la O-methyl-6 erythromycine A) qui se cyclise ensuite entre C-11 et C-12 par une reaction de Michael intramoleculaire

(1976). A RAPID, CONVENIENT, HIGH YIELD PROCEDURE FOR THE REGENERATION OF 2,3-DICHLORO-5,6-DICYANOBENZOQUINONE (DDQ) FROM THE CORRESPONDING HYDROQUINONE (DDHQ) Organic Preparations and Procedures International: Vol. 8, No. 3, pp. 141-143.