Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation.

Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies.

Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: use of a conformation-based hypothesis to facilitate compound design.

Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.

The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: the second clinical candidate having a shorter and favorable human half-life.

In this Letter, we provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX-2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1t(1/2)=360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t(1/2)=34 h.

Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning.

Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.

A survey of scholarly literature describing the field of bioinformatics education and bioinformatics educational research.

Bioinformatics education can be broadly defined as the teaching and learning of the use of computer and information technology, along with mathematical and statistical analysis for gathering, storing, analyzing, interpreting, and integrating data to solve biological problems. The recent surge of genomics, proteomics, and structural biology in the potential advancement of research and development in complex biomedical systems has created a need for an educated workforce in bioinformatics. However, effectively integrating bioinformatics education through formal and informal educational settings has been a challenge due in part to its cross-disciplinary nature. In this article, we seek to provide an overview of the state of bioinformatics education. This article identifies: 1) current approaches of bioinformatics education at the undergraduate and graduate levels; 2) the most common concepts and skills being taught in bioinformatics education; 3) pedagogical approaches and methods of delivery for conveying bioinformatics concepts and skills; and 4) assessment results on the impact of these programs, approaches, and methods in students' attitudes or learning. Based on these findings, it is our goal to describe the landscape of scholarly work in this area and, as a result, identify opportunities and challenges in bioinformatics education.

Construction of a drug safety assurance information system based on clinical genotyping.

To capitalize on the vast potential of patient genetic information to aid in assuring drug safety, a substantial effort is needed in both the training of healthcare professionals and the operational enablement of clinical environments. Our research aims to satisfy these needs through the development of a drug safety assurance information system (GeneScription) based on clinical genotyping that utilizes patient-specific genetic information to predict and prevent adverse drug responses. In this paper, we present the motivations for this work, the algorithms at the heart of GeneScription, and a discussion of our system and its uses. We also describe our efforts to validate GeneScription through its evaluation by practicing pharmacists and pharmacy professors and its repeated use in training pharmacists. The positive assessment of the GeneScription software tool by these domain experts provides strong validation of the importance, accuracy, and effectiveness of GeneScription.

Pharmacogenomics training using an instructional software system.

OBJECTIVES: To implement an elective course in pharmacogenomics designed to teach pharmacy students about the fundamentals of pharmacogenomics and the anticipated changes it will bring to the profession. DESIGN: The 8 sessions of the course covered the basics of pharmacogenomics, genomic biotechnology, implementation of pharmacogenetics in pharmacy, information security and privacy, ethical issues related to the use of genomic data, pharmacoepidemiology, and use and promotion of GeneScription, a software program designed to mimic the professional pharmacy environment. ASSESSMENT: Student grades were based on completion of a patient education pamphlet, a 2-page paper on pharmacogenomics, and precourse and postcourse survey instruments. In the postcourse survey, all students strongly agreed that genomic data could be used to determine the optimal dose of a drug and genomic data for metabolizing enzymes could be stored in a safe place. Students also were more willing to submit deoxyribonucleic acid (DNA) data for genetic profiling and better understood how DNA analysis is performed after completing the course. CONCLUSIONS: An elective course in pharmacogenomics equipped pharmacy students with the basic knowledge necessary to make clinical decisions based on pharmacogenomic data and to teach other healthcare professionals and patients about pharmacogenomics. For personalized medicine to become a reality, all pharmacists and pharmacy students must learn this knowledge and these skills.

Drug safety assurance through clinical genotyping: near-term considerations for a system-wide implementation of personalized medicine.

The rationale and overall system-wide behavior of a clinical genotyping information system (both DNA analysis and data management) requires a near-term, scalable approach, which is emerging in the focused implementation of pharmacogenomics and drug safety assurance. The challenges to implementing a successful clinical genotyping system are described, as are how the benefits of a focused, near-term system for drug safety assessment and assurance overcome the logistical and operational challenges that perpetually hinder the development of a societal-scale clinical genotyping system. This rationale is based on the premise that a focused application domain for clinical genotyping, specifically drug safety assurance, provides a transition paradigm for both professionals and consumers of healthcare, thereby facilitating the movement of genotyping from bench to bedside and paving the way for the adoption of prognostic and diagnostic applications in clinical genomics.