Arthur Doweyko

Indian River State College · Biological Sciences

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evalu...

Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over...

Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated...

SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards...

A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide fl...

Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cy...

Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.

A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 3...

The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation requir...

The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly effi...

The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor....

Humankind has been in the business of discovering drugs for thousands of years. At present, small-molecule drug design is based on specific macromolecular receptors as targets for inhibition or modulation. To this end, a number of clever approaches have evolved over time: computer-aided techniques including structure-activity relationships and synt...

A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which...

The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole...

The concept of quantitative SAR (QSAR) is inherently imbued with an expectation of predictivity, novel insights and the generation of useful hypotheses, particularly as applied to the drug discovery process. However, even recently developed QSAR models often appear to be flawed, characterized by mediocre predictive power and undecipherable descript...

A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revea...

The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2...

A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.

Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The p...

A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of comp...

This perspective concerns the methods employed within the current drug discovery community to develop predictive quantitative structure-activity relationships (QSAR). Specifically, a number of cautions are provided which may circumvent misuse and misunderstanding of the technique. Ignorance of such caveats has led to a discouraging tendency of the...

A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based T...

The synthesis and structure-activity relationships (SAR) of p38alpha MAP kinase inhibitors based on heterobicyclic scaffolds are described. This effort led to the identification of compound (21) as a potent inhibitor of p38alpha MAP kinase with good cellular potency toward the inhibition of TNF-alpha production. X-ray co-crystallography of an oxala...

We describe the development of a computational model for the prediction of the inhibition of K(+) flow through the hERG ion channel. Using a collection of 1075 discovery compounds with hERG inhibition measured in our standard patch-clamp electrophysiology assay, molecular features important for drug-induced inhibition were identified using a combin...

Nuclear hormone receptors (NHRs) regulate gene expression by forming complexes with small molecule ligands, other proteins, and DNA. Specific ligands, which include steroids, thyroids, and retinoids, are responsible for the regulation of complex processes in cellular differentiation, homeostasis, reproduction, and development. NHRs responding to st...

A novel series of potent dual agonists of PPARalpha and PPARgamma, the alkoxybenzylglycines, was identified and explored using a solution-phase library approach. The synthesis and structure-activity relationships of this series of dual PPARalpha/gamma agonists are described.

Solvent entropy change is a major factor in driving the association of hydrophobic species in aqueous solutions. We have developed a novel methodology which simulates the solvation of hydrophobic surfaces by water. A system of virtual solvent particles surrounding the solute governed by arbitrarily determined rules provides a means to estimate the...

2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and ce...

Bioorganic & Medicinal Chemistry Letters 16 (2006) 41480960-894X/$ - see front matter 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.bmcl.2006.05.004DOI of original article: 10.1016/j.bmcl.2006.01.115.*Corresponding author. Tel.: +1 609 252 5068; fax: +1 609 252 6804; e-mail: jagabandhu.das@bms.com

A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity, and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 3 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced...

A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 2 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced I...

Scheme 4 contains an incorrect structure for compound 26, where the structure contains a methoxy in the C-6 0 position. This compound would not be expected to be active. The legend describing the synthesis of compound 26 is correct, and if one follows the logic of the synthesis, it is apparent that compound 26 should have a hydroxy at C-6 0 instead...

High affinity thyromimetics containing a novel phenyl-naphthylene core are reported. The functionalized core is readily accessible via a Suzuki coupling protocol. Examples of this new class of TR ligands have sub-nanomolar binding affinities for the TRbeta receptor and low to modest selectivity for TRbeta. They also exhibit an SAR that diverges fro...

A novel class of 5-cyanopyrimidine-based inhibitors of p38alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (>50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior t...

Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR alpha/gamma dual agonist that shows potent activity in vitro at human PPARalpha (EC(50) = 320 nM) and PPARgamma(EC(50) = 110 nM). Compound 2 shows excellent efficacy for lowering glucose, insulin, triglycerides, and free fatty acids in genetically obese, severely diabet...

Small molecule inhibition of protein kinases in the treatment of significant diseases such as cancer, Alzheimer's disease, diabetes, and rheumatoid arthritis has attracted significant attention over the past two decades and has clearly become one of the most significant challenges for drug discovery in the 21st century. While the recent identificat...

A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete...

A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing i...

A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56 Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy. A series of substituted 2-(aminoheteroaryl)- thiazole-5-carboxamide analogs have been synthesized as...

Nonreceptor protein tyrosine kinases including Lck, ZAP-70, and Itk play essential roles in T-cell receptor (TCR) signaling. Gene knockout studies have revealed that mice lacking these individual kinases exhibit various degrees of immunodeficiency; however, highly selective small molecule inhibitors of these kinases as potential immunosuppressive a...

A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vi...

A set of thyromimetics having improved selectivity for TR-beta1 were prepared by replacing the 3'-isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3'-phenyl moiety bearing small hydrophobic groups meta to the...

3D-QSAR is typically used to construct models (1) to predict activities, (2) to illustrate significant regions, and (3) to provide insight into possible interactions. To the contrary, examples are described herein which make it clear that the predictivity of such models remains elusive, that so-called significant regions are subject to the vagaries...

A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.

A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) was prepared to elucidate their structure-activity relationships (SAR), selectivity and cell activity in the T-cell proliferation assay. BMS-350751 (2) and BMS-358233 (3) are identified as potent Lck inhibitors with excellent cellular activities against T-cell...

A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in the T-cell proliferation assay. BMS-243117 (compound 2) is identified as a potent, and selective Lck inhibitor with good cellular activity (IC(50)=1.1 mic...

By way of example, we discuss the apparent 'failure' of in silico ADME/Tox models and attempt to understand the causes. Often, the interpretation of the success of models lies in their use and the expectations of the user. Other times, models are, in fact, of little value. Disappointing results can be linked to the key aspects of the model and mode...

We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.

The observed 5-HT1A and alpha1-adrenergic receptor (alpha1-AR) receptor binding properties of a series of 23 thienopyrimidinones were used to develop HASL 3D-QSAR models. A single, low energy conformer of the most active analogue in the series, which was consistent with NMR structural studies, was chosen as a template molecule. Alignments of all th...

The observed 5-HT1A and 1-adrenergic receptor (1-AR) receptor binding properties of a series of 23 thienopyrimidinones were used to develop HASL 3D-QSAR models. A single, low energy conformer of the most active analogue in the series, which was consistent with NMR structural studies, was chosen as a template molecule. Alignments of all the molecule...

The precise function of the 5-HT receptors remains undefined, and progress toward this has been hampered by the lack of selective ligands.

Two three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL), were compared with respect to the analysis of a training set of 154 artemisinin analogues. Five models were created, including a complete HASL and two trimmed versions, as we...

A number of substituted imidazo[1,2-a]pyridines and related analogues were selected for analysis of their in vitro biochemical and in vivo gastric antisecretory activity using comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL) methodologies. The training set of compounds selected included those that were also c...

The application of HASL (hypothetical active site lattice) methodology has been successfully extended to generate putative pharmacophoric patterns in three dimensions capable of quantitatively predicting binding activity. The transformation of a HASL model to a pharmacophore is illustrated using pKi values published for 84 HIV-1 protease inhibitors...

The application of HASL (hypothetical active site lattice) methodology has been successfully extended to generate putative pharmacophoric patterns in three dimensions capable of quantitatively predicting binding activity. The transformation of a HASL model to a pharmacophore is illustrated using pK(i) values published for 84 HIV-1 protease inhibito...

The sequence specificity of DNA alkylation by uracil mustard was examined using a novel three-dimensional QSAR method known as HASL, or the hypothetical active site lattice. The structures of a variety of 4-mer sequences obtained from pBR322 and SV40 were related to their degree of guanine-N7 alkylation by uracil mustard. The resulting correlations...

A novel three-dimensional QSAR technique (HASL) is described. HASL (Hypothetical Active Site Lattice) represents a composite description of a macromolecular binding site obtained from ligand molecule structures and activities. The scope and limitations of the method are discussed by means of its application to in vitro and in vivo data.

The sulfoximides (III) are prepared by reaction of the sulfoxides (I) with the azide (II) and sulfuric acid.

The phosphonate analogues of methionine and buthionine sulfoximide were synthesized by the action of NaN3 on the corresponding sulfoxides. Analogues 3 and 4 were prepared to determine the effect of altering the carboxyl portion of known inhibitors in the glutamate synthase cycle. Results of biological testing revealed that 3 and 4 did not posses th...

Microcomputer-assisted methods are described that allow the mathematical construction of a hypothetical active site lattice (HASL) which can model enzyme-inhibitor interactions and provides predictive structure-activity relationships for a set of competitive inhibitors. The inhibitor set can be structurally dissimilar, including acyclic and cyclic...

Phenyl-substituted analogues of 2-[(phenylmethyl)sulfonyl]pyridine 1-oxide preemergent herbicides were examined in order to determine quantitative relationships between structure and activity against the following three weed species: switch grass (Panicum virgatum L.), barnyard grass (Echinochloa crusgalli L. Beauv.), and green foxtail (Setaria vir...

The reaction of chloromethyl benzoates with sodium pyrithione afforded (2-pyridylthio)methyl benzoate N-oxides having in vitro fungicidal activity on a variety of agriculturally important fungi (e.g., Alternaria solani and Phytophthora infestans). The title compounds have demonstrated a spectrum of activity similar to that of zinc pyrithione, sugge...

Aus den Sulfonen (II) erhält man mit Tetrahalogenmethanen oder mit Alkylierungsmitteln in NaOH/DMF die Halogen- (I) bzw. die substituierten Sulfone (IV).

In the presence of the general bases imidazole and phosphate dianion methyl- and phenylglyoxalglutathionylhemithiol acetals rearrange to the corresponding S-lactoyl- and S-mandeloylglutathiones, respectively, and then hydrolyze to the corresponding acids. NMR-detected incorporation of solvent protons indicates the mechanism of the arrangement to be...

Synthesis of a series of alpha-hydroxythiol esters made available, for the first time, product-like molecules that were evaluated as inhibitors of the enzyme glyoxalase I and as potential antitumor agents. All the alpha-hydroxythiol esters tested were competitive inhibitors of the enzyme, albeit weak; however, the relative [I]50 values suggested in...

Aus den Glyoxalen (I) erhält man mit den Mercaptanen (II) die Addukte (III), die in DMF mit 2,6-Dimethylpyridin zu den Thiolo-hydroxy-estern (IV) führen.

Typescript. Thesis--Rutgers University, 1976. Vita. Includes bibliographical references.