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Biomedical subjects

Arthur M Doweyko

Publications and source records attributed to Arthur M Doweyko.

16 recordsLinked to original sources
PubMed2006

2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor.

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 cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.

Administration, Oral↗
PubMed2006

Discovery and SAR of 2-amino-5-(thioaryl)thiazoles as potent and selective Itk inhibitors.

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 IL-2 production in mice in vivo and was previously reported to reduce lung inflammation in a mouse model of ovalbumin induced allergy/asthma.

Animals↗
PubMed2005

A new class of high affinity thyromimetics containing a phenyl-naphthylene core.

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 from other thyromimetics that are based on the diaryl ether core found in 3,5,3'-triiodothyronine.

Models, Molecular↗
PubMed2005

5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.

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 to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38alpha.

Administration, Oral↗
PubMed2005

Structural comparison of p38 inhibitor-protein complexes: a review of recent p38 inhibitors having unique binding interactions.

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 identification of 518 different kinases in the human genome has offered a wealth of opportunities for drug intervention in the treatment of these diseases, it has also created a daunting challenge with respect to selective kinase inhibition as a viable strategy in target-based drug design. Over the past decade, the design and development of a small molecule that selectively inhibits the p38 mitogen activated protein (MAP) kinase has clearly emerged as one of these challenges within the industry. This review will focus on the comparison of the x-ray crystal structures and binding models of the most recent p38 inhibitor-enzyme complexes and the identification of the structural elements and interactions that may be important in providing inhibitor potency and selectivity toward the p38 MAP kinase.

Benzamides↗
PubMed2004

Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.

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 tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.

Adenosine Triphosphate↗
PubMed2004

Imidazoquinoxaline Src-family kinase p56Lck inhibitors: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- [1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity.

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 vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.

Animals↗
PubMed2004

Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta.

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 biphenyl link. X-ray crystal data of 15c complexed with TR-beta1 LBD shows methionine 442 to be displaced by the bulky R3' phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand-receptor complex retains full agonist activity.

2-Propanol↗
PubMed2003

Discovery of 2-amino-heteroaryl-benzothiazole-6-anilides as potent p56(lck) inhibitors.

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 proliferation.

Anilides↗
PubMed2003

Molecular design, synthesis, and structure-Activity relationships leading to the potent and selective p56(lck) inhibitor BMS-243117.

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 microM) against T-cell proliferation.

Adenosine Triphosphate↗
PubMedDate not supplied

3D-QSAR illusions.

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 of alignment, and that the nature of possible interactions heavily depends on the eye of the beholder. Although great strides have been made in the imaginative use of 3D-descriptors, 3D-QSAR remains largely a retrospective analytical tool. The arbitrary nature of both the alignment paradigm and atom description lends itself to capricious models, which in turn can lead to distorted conclusions. Despite these illusionary pitfalls, predictions can be enhanced when the test set is bounded by the descriptor space represented in the training set. Interpretation of significant interaction regions becomes more meaningful when alignment is constrained by a binding site. Correlations obtained with a variety of atom descriptors suggest choosing useful ones, in particular, in guiding synthetic effort.

Models, Molecular↗
PubMedDate not supplied

A novel method to simulate the hydrophobic effect and its application to the ranking of host/guest complexes.

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 degree of order (Q) imposed by such solvation. Computed changes in Q (dQ) upon complex formation have been found to correlate well with observed binding affinities of host-guest complexes in aqueous solutions. Examples are described which illustrate the ability of dQ calculations to identify the correct ligand pose from a set of decoy complexes as well as provide rank ordering of a set of highly diverse ligand-protein complexes. Comparisons to surface-area-based calculations are discussed. The Q methodology holds great promise in the development of predictive structure-based approaches to drug design, as it provides a relatively simple means to estimate the hydrophobic effect.

Algorithms↗