Core Modifications of GSK3335103 toward Orally Bioavailable αβ Inhibitors with Improved Synthetic Tractability.

The αβ integrin has been identified as a target for the treatment of fibrotic diseases, based on the role it has in activating TGF-β, a protein implicated in the pathogenesis of fibrosis. However, the development of orally bioavailable αβ inhibitors has proven challenging due to the zwitterionic pharmacophore required to bind to the RGD binding site. This work describes the design and development of a novel, orally bioavailable series of αβ inhibitors, developing on two previously published αβ inhibitors, GSK3008348 and GSK3335103.

Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic αβ Integrin Inhibitors.

A series of 3-aryl(()-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable αβ integrin inhibitors. Starting from a zwitterionic peptidomimetic series optimized for inhaled administration, the balancing of potency and passive permeability to achieve suitable oral agents through modification and exploration of aryl substituents and p of the central cyclic amine is described. ()-4-(()-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid was found to have highly desirable oral pharmacokinetic profiles in rat, dog, and minipig, with low to moderate clearance (26%, 7%, and 18% liver blood flow, respectively), moderate volumes of distribution (3.

High-Resolution Monitoring of Scour Using a Novel Fiber-Optic Distributed Temperature Sensing Device: A Proof-of-Concept Laboratory Study.

Scour events can severely change the characteristics of streams and impose detrimental hazards on any structures built on them. The development of robust and accurate devices to monitor scour is therefore essential for studying and developing mitigation strategies for these adverse consequences. This technical note introduces a novel scour-monitoring device that utilizes new advances in the fiber-optic distributed temperature sensing (FO-DTS) technology.

How Diverse Is Medicinal Chemistry? Insights into Race, Ethnicity, Origin, Gender, and Geography.

A bibliometric study of authors across medicinal chemistry journals over 20 years reveals important trends. Most United States (US) based authors are assigned as racially/ethnically Asian or White; few are Black or Hispanic. More US coauthors have the same race/ethnicity as the corresponding author than expected.

Pharmacological characterisation of GSK3335103, an oral αvβ6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease.

Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ) via the alpha-V beta-6 (αvβ6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvβ6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated.

Emerging therapeutic opportunities for integrin inhibitors.

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis.

Metastatic Neuroblastoma Presenting as a Submandibular Mass with Mandibular Bone Involvement in a Three-Year-Old Child.

Although neuroblastoma is one of the most common extra-cranial tumors in the pediatric population, it is rarely seen as a metastasis to the mandibular bone. The following is a case report of a 3-year-old male who initially presented with a submandibular mass that was proven to be a poorly differentiated metastatic neuroblastoma through excisional biopsy. This report is one of the few case reports that demonstrates metastatic submandibular neuroblastoma with mandibular bone involvement in the pediatric population.

Writing Your Next Medicinal Chemistry Article: Journal Bibliometrics and Guiding Principles for Industrial Authors.

Writing scientific articles is immensely rewarding but challenging. This Perspective provides the medicinal chemist with background and advice on the art and process of writing manuscripts and complements the instructions to authors provided by journals. Included are many tips that we wish we had known when we first started writing.

Sprinkling the pixie dust: reflections on innovation and innovators in medicinal chemistry and drug discovery.

Pharmaceutical innovation is in short supply. Many diagnoses have been made and remedies prescribed by those in the industry and those that comment on it. There is much less practical advice for the individual about becoming more innovative or managing innovation at the laboratory level, which is where new medicines are discovered.

The Design of Potent, Selective and Drug-Like RGD αvβ1 Small-Molecule Inhibitors Derived from non-RGD α4β1 Antagonists.

Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvβ1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identification of non-RGD hit small-molecule αvβ1 inhibitors.

Analysis of 334 Cases of Pediatric Esophageal Foreign Body Removal Suggests that Traditional Methods Have Similar Outcomes Whereas a Magnetic Tip Orogastric Tube Appears to Be an Effective, Efficient, and Safe Technique for Disc Battery Removal.

Procedures and outcomes for pediatric esophageal foreign body removal were analyzed. Traditional methods of battery removal were compared with a magnetic tip orogastric tube (MtOGT). A single institution retrospective review from 1997 to 2014 of pediatric patients with esophageal foreign bodies was performed.

Aesthetic Unit Boundary Approach to Large Fibroadenoma Resection.

Background: Fibroadenomas are the most common benign breast tumors in adolescents. Surgical excision is indicated when the tumor becomes large or symptomatic. Multiple approaches have been described.

Mesh nebulizers have become the first choice for new nebulized pharmaceutical drug developments.

In the 24 years since first being marketed, the mesh nebulizer has been developed by five main manufacturers into a viable solution for the delivery of high-value nebulized drugs. Mesh nebulizers provide increased portability, convenience and energy efficiency along with similar lung deposition and increased ease of use compared with jet nebulizers. An analysis of EU and US clinical trial databases has shown that mesh nebulizers are now preferred over jet nebulizers for clinical trials sponsored by pharmaceutical companies.

Delay Between Shaking and Actuation of a Hydrofluoroalkane Fluticasone Pressurized Metered-Dose Inhaler.

Background: Inhaled corticosteroids are used to treat pediatric asthma. The shaking of a pressurized metered-dose inhaler (pMDI) is required to ensure consistency of emitted dose. Delays between shaking and actuating the pMDI are frequent during administration of aerosols to children where a valved holding chamber is used.

Differences in the Management of Perforated Appendicitis in Children by Race and Insurance Status.

This study was conducted to assess whether race and socioeconomic status influence the management method used to treat pediatric perforated appendicitis. Nonelective pediatric admissions with a primary diagnosis of appendicitis were analyzed using data from the 2001-2010 Nationwide Inpatient Sample. Bivariate and multivariate analyses were used to determine the association between race, insurance status, median household income, rural/metropolitan location, and the risk adjusted odds of undergoing surgery, laparoscopic appendectomy, percutaneous drainage, or neither surgery nor percutaneous drainage.

An αv-RGD Integrin Inhibitor Toolbox: Drug Discovery Insight, Challenges and Opportunities.

There is a requirement for efficacious and safe medicines to treat diseases with high unmet need. The resurgence in αv-RGD integrin inhibitor drug discovery is poised to contribute to this requirement. However, drug discovery in the αv integrin space is notoriously difficult due to the receptors being structurally very similar as well as the polar zwitterionic nature of the pharmacophore.

A simple method for assaying colistimethate sodium in pharmaceutical aerosol samples using high performance liquid chromatography.

A rapid and simple reversed-phase high performance liquid chromatography (HPLC) method for the quantitation of colistimethate sodium in pharmaceutical formulations has been developed. The chromatographic separation was performed using a Phenomenex Kinetex XB-C18 column with gradient elution using a mobile phase containing acetonitrile and 32mM sodium sulphate. Quantitation is based on the sum of the areas of two prominent peaks in the chromatogram, which produces a total peak area that is stable for 120 sample injections.

Variability in delivered dose and respirable delivered dose from nebulizers: are current regulatory testing guidelines sufficient to produce meaningful information?

Background: To improve convenience to patients, there have been advances in the operation of nebulizers, resulting in fast treatment times and less drug lost to the environment. However, limited attention has been paid to the effects of these developments on the delivered dose (DD) and respirable delivered dose (RDD). Published pharmacopoeia and ISO testing guidelines for adult-use testing utilize a single breathing pattern, which may not be sufficient to enable effective comparisons between the devices.

Drug Delivery in Asthmatic Children Following Coordinated and Uncoordinated Inhalation Maneuvers: A Randomized Crossover Trial.

Background: Valved holding chambers (VHCs) are used in children to deliver pressurized metered dose inhalers (pMDI). In vitro data suggest that uncoordinated use decreases the amount of drug available for inhalation. We hypothesize that in an ex vivo study, the coordinated maneuver will deliver more drug than the uncoordinated one.