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Biomedical subjects

Paul Weller

Publications and source records attributed to Paul Weller.

8 recordsLinked to original sources
PubMed2006

Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase.

A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38alpha established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.

Adenosine Triphosphate↗
PubMed2006

In silico pharmacogenetics of warfarin metabolism.

Pharmacogenetic approaches can be instrumental for predicting individual differences in response to a therapeutic intervention. Here we used a recently developed murine haplotype-based computational method to identify a genetic factor regulating the metabolism of warfarin, a commonly prescribed anticoagulant with a narrow therapeutic index and a large variation in individual dosing. After quantification of warfarin and nine of its metabolites in plasma from 13 inbred mouse strains, we correlated strain-specific differences in 7-hydroxywarfarin accumulation with genetic variation within a chromosomal region encoding cytochrome P450 2C (Cyp2c) enzymes. This computational prediction was experimentally confirmed by showing that the rate-limiting step in biotransformation of warfarin to its 7-hydroxylated metabolite was inhibited by tolbutamide, a Cyp2c isoform-specific substrate, and that this transformation was mediated by expressed recombinant Cyp2c29. We show that genetic variants responsible for interindividual pharmacokinetic differences in drug metabolism can be identified by computational genetic analysis in mice.

Animals↗
PubMed2006

Understanding our drugs and our diseases.

Analysis of mouse genetic models of human disease-associated traits has provided important insight into the pathogenesis of human disease. As one example, analysis of a murine genetic model of osteoporosis demonstrated that genetic variation within the 15-lipoxygenase (Alox15) gene affected peak bone mass, and that treatment with inhibitors of this enzyme improved bone mass and quality in rodent models. However, the method that has been used to analyze mouse genetic models is very time consuming, inefficient, and costly. To overcome these limitations, a computational method for analysis of mouse genetic models was developed that markedly accelerates the pace of genetic discovery. It was used to identify a genetic factor affecting the rate of metabolism of warfarin, an anticoagulant that is commonly used to treat clotting disorders. Computational analysis of a murine genetic model of narcotic drug withdrawal suggested a potential new approach for treatment of narcotic drug addiction. Thus, the results derived from computational mouse genetic analysis can suggest new treatment strategies, and can provide new information about currently available medicines.

Animals↗
PubMed2005

Pseudotumorous folliculotropic mycosis fungoides.

Fungating nodules and infiltrated plaques are usually equated with advanced tumor stage mycosis fungoides. We report an 85-year-old man who presented in this way but multiple skin biopsies revealed that the bulk of his nodules were due to marked follicular hyperplasia as a result of folliculotropic mycosis fungoides. This clinical presentation may be best described as a pseudotumorous form of mycosis fungoides dominated by follicular epithelial hyperplasia rather than lymphocytic proliferation characteristic of true tumor stage disease. Similar presentations have been described as a verrucous and hyperplastic variant of mycosis fungoides due to the presence of prominent epidermal hyperplasia.

Aged↗
PubMed2005

Pharmacogenomics and drug development.

It is generally anticipated that pharmacogenomic information will have a large impact on drug development and will facilitate individualized drug treatment. However, there has been relatively little quantitative modeling to assess how pharmacogenomic information could be best utilized in clinical practice. Using a quantitative model, this review demonstrates that efficacy is increased and toxicity is reduced when a genetically-guided dose adjustment strategy is utilized in a clinical trial. However, there is limited information available regarding the genetic variables affecting the disposition or mechanism of action of most commonly used medications. These genetic factors must be identified to enable pharmacogenomic testing to be routinely used in the clinic. A recently described murine haplotype-based computational genetic analysis method provides one strategy for identifying genetic factors regulating the pharmacokinetics and pharmacodynamics of commonly used medications.

Animals↗
PubMed2004

Rational design of 6-methylsulfonylindoles as selective cyclooxygenase-2 inhibitors.

The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.

Administration, Oral↗
PubMed2003

Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase.

Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.

Administration, Oral↗