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. The percentage of female authors increased globally, but only slowly. Since 2010, the number of female and male authors declined by 9% and 30%, respectively. Geographically, most authors are male except in Italy where there is gender balance. Gender homophily is observed globally. Geographically, the discipline is now more widely practiced. Article output doubled from 2000 to 2010 with a large increase in articles from China. China excepted, output has since declined. The average number of authors per article rose by a third since 2000. The value of high diversity groups in education, research, and industry cannot be overstated. We recommend diversity is addressed by every medicinal chemist.

Pharmacological characterisation of GSK3335103, an oral αvß6 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-ß (TGFß) via the alpha-V beta-6 (αvß6) 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 αvß6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated. As part of a medicinal chemistry programme GSK3335103 was identified and profiled in a range of pre-clinical in vitro and in vivo systems. GSK3335103 was shown to bind to the αvß6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of αvß6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the αvß6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the αvß6 integrin and inhibit the activation of TGFß in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by αvß6 engagement, TGFß signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent αvß6 inhibitor that attenuates TGFß signalling in vitro and in vivo with a well-defined pharmacokinetic/pharmacodynamic relationship. This translates to a significant reduction of collagen deposition in vivo and therefore GSK3335103 represents a potential novel oral therapy for fibrotic disorders.

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. Bibliometric data from seven medicinal chemistry journals between 2000 and 2019 are collated including Bioorganic and Medicinal Chemistry Letters and the Journal of Medicinal Chemistry. Although the overall number of articles has doubled, the output from 23 large pharma companies in the past decade has dropped significantly. Commentary is given on the entire process of writing original scientific articles, opinion articles, and reviews. Examples from our own papers and experience are shared including what typically motivates the writer, challenges commonly encountered, and how we find time to write. Finally, the benefits derived from much wider publishing of industrial medicinal chemistry are described.

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. This article collates and reviews ideas selected from the literature and encountered over many years by medicinal chemists, team leaders and project leaders in a big pharma.

The Design of Potent, Selective and Drug-Like RGD αvß1 Small-Molecule Inhibitors Derived from non-RGD α4ß1 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 αvß1 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 αvß1 inhibitors. We show that αvß1 activity is embedded in a range of published α4ß1 (VLA-4) ligands; we also demonstrate how a non-RGD integrin inhibitor (of α4ß1 in this case) was converted into a potent non-zwitterionic RGD integrin inhibitor (of αvß1 in this case). We designed urea ligands with excellent selectivity over α4ß1 and the other αv integrins (αvß3, αvß5, αvß6, αvß8). In silico docking models and density functional theory (DFT) calculations aided the discovery of the lead urea series.

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. This Review aims to guide drug discovery research in this field through an αv inhibitor toolbox, consisting of small molecules and antibodies. Small-molecule αv tool compounds with extended profiles in αvß1, 3, 5, 6 and 8 cell adhesion assays, with key physicochemical properties, have been collated to assist in the selection of the right tool for the right experiment. This should also facilitate an understanding of partial selectivity profiles of compounds generated in different assays across research institutions. Prospects for further αv integrin research and the critical importance of target validation are discussed, where increased knowledge of the selectivity for individual RGD αv integrins is key. Insights into the design of small-molecule RGD chemotypes for topical or oral administration are provided and clinical findings on advanced molecules are examined.

Dissecting fibrosis: therapeutic insights from the small-molecule toolbox.

Fibrosis, which leads to progressive loss of tissue function and eventual organ failure, has been estimated to contribute to ~45% of deaths in the developed world, and so new therapeutics to modulate fibrosis are urgently needed. Major advances in our understanding of the mechanisms underlying pathological fibrosis are supporting the search for such therapeutics, and the recent approval of two anti-fibrotic drugs for idiopathic pulmonary fibrosis has demonstrated the tractability of this area for drug discovery. This Review examines the pharmacology and structural information for small molecules being evaluated for lung, liver, kidney and skin fibrosis. In particular, we discuss the insights gained from the use of these pharmacological tools, and how these entities can inform, and probe, emerging insights into disease mechanisms, including the potential for future drug combinations.

2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 3. Synthesis, pharmacokinetics, and in vivo potency.

A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.

2,5-Diketopiperazines as potent and selective oxytocin antagonists 1: Identification, stereochemistry and initial SAR.

This paper covers efforts to discover orally active potent and selective oxytocin antagonists. Screening pooled libraries identified a novel series of 2,5-diketopiperazine derivatives with antagonist activity at the human oxytocin receptor. We report the initial structure-activity relationship investigations and the determination of the stereochemistry of the most potent compounds.