RESUMO
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.
Assuntos
Autoria/normas , Química Farmacêutica/normas , Etnicidade/estatística & dados numéricos , Publicações Periódicas como Assunto/estatística & dados numéricos , Publicações/estatística & dados numéricos , Grupos Raciais/estatística & dados numéricos , Feminino , Geografia , Humanos , Masculino , Estados UnidosRESUMO
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.
Assuntos
Antifibróticos/farmacologia , Integrinas/antagonistas & inibidores , Fibrose Pulmonar/tratamento farmacológico , Administração Oral , Animais , Antifibróticos/química , Antifibróticos/uso terapêutico , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Disponibilidade Biológica , Bleomicina/administração & dosagem , Bleomicina/toxicidade , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Integrinas/química , Integrinas/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lisossomos/metabolismo , Masculino , Camundongos , Oligopeptídeos/química , Cultura Primária de Células , Proteólise/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
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.
Assuntos
Autoria , Bibliometria , Química Farmacêutica , EditoraçãoRESUMO
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.
Assuntos
Química Farmacêutica/métodos , Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , Animais , Descoberta de Drogas/tendências , Indústria Farmacêutica/tendências , Humanos , Pesquisa/tendênciasRESUMO
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). Inâ silico docking models and density functional theory (DFT) calculations aided the discovery of the lead urea series.
Assuntos
Fenilalanina/análogos & derivados , Receptores de Vitronectina/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Sítios de Ligação , Desenho de Fármacos , Estabilidade de Medicamentos , Humanos , Ligantes , Fígado/metabolismo , Masculino , Fenilalanina/síntese química , Fenilalanina/metabolismo , Ratos Sprague-Dawley , Receptores de Vitronectina/química , Receptores de Vitronectina/metabolismo , Ureia/síntese química , Ureia/metabolismoRESUMO
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.
Assuntos
Descoberta de Drogas , Integrina alfaV/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Humanos , Integrina alfaV/química , Modelos Moleculares , OligopeptídeosRESUMO
Cystic fibrosis (CF) is a major lethal genetic disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR). This encodes a chloride ion channel on the apical surface of epithelial cells. The most common mutation in CFTR (F508del-CFTR) generates a protein that is misfolded and retained in the endoplasmic reticulum. Identifying small molecules that correct this CFTR trafficking defect is a promising approach in CF therapy. However, to date only modest efficacy has been reported for correctors in clinical trials. We identified the marine sponge metabolite latonduine as a corrector. We have now developed a series of latonduine derivatives that are more potent F508del-CFTR correctors with one (MCG315 [2,3-dihydro-1H-2-benzazepin-1-one]) having 10-fold increased corrector activity and an EC50 of 72.25 nM. We show that the latonduine analogs inhibit poly-ADP ribose polymerase (PARP) isozymes 1, 3, and 16. Further our molecular modeling studies point to the latonduine analogs binding to the PARP nicotinamide-binding domain. We established the relationship between the ability of the latonduine analogs to inhibit PARP-16 and their ability to correct F508del-CFTR trafficking. We show that latonduine can inhibit both PARP-3 and -16 and that this is necessary for CFTR correction. We demonstrate that latonduine triggers correction by regulating the activity of the unfolded protein response activator inositol-requiring enzyme (IRE-1) via modulation of the level of its ribosylation by PARP-16. These results establish latonduines novel site of action as well as its proteostatic mechanism of action.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Adenosina Difosfato Ribose/metabolismo , Animais , Proteínas de Ciclo Celular/química , Linhagem Celular , Endorribonucleases/metabolismo , Técnicas de Silenciamento de Genes , Glicoproteínas/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Modelos Moleculares , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/química , Transporte Proteico/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
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.
Assuntos
Descoberta de Drogas , Fibrose/tratamento farmacológico , Humanos , Rim/patologia , Cirrose Hepática/tratamento farmacológico , Miofibroblastos/patologia , Estresse Oxidativo , Fibrose Pulmonar/tratamento farmacológicoRESUMO
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.
Assuntos
Indenos/síntese química , Piperazinas/síntese química , Receptores de Ocitocina/antagonistas & inibidores , Administração Oral , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Ligação Competitiva , Disponibilidade Biológica , Células CHO , Sinalização do Cálcio/efeitos dos fármacos , Cricetinae , Cricetulus , Cães , Humanos , Indenos/farmacocinética , Indenos/farmacologia , Ocitocina/farmacologia , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Contração Uterina/efeitos dos fármacosRESUMO
A palladium catalyzed C-H bond functionalization system that operates under ambient and aerobic conditions can be used to alkenylate pyrroles with control of regioselectivty. A steric and electronic control strategy can be used to influence positional control in the C-H bond functionalization process that results in either the C2 or C3 alkenylated products. Air, molecular oxygen, or tBuOOBz can be used as reoxidant in this mild process, and the reaction works on a range of substrates. Finally a catalytic aerobic annulation strategy is described that can be controlled to produce cyclization at either the C2 or C3 positions, thus forming diverse pyrrole products.
Assuntos
Alcenos/síntese química , Paládio/química , Pirróis/síntese química , Aerobiose , Alcenos/química , Catálise , Cátions Bivalentes , Oxirredução , Pirróis/químicaRESUMO
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.