ABSTRACT
OBJECTIVE: The Asia-Pacific region (APAC) represents a unique environment for the publication of biomedical research, particularly industry-funded research. Awareness and adoption of international guidelines on ethical publication practices continues to increase across APAC, but the reframing and expansion of many of the recommendations in the Good Publication Practice (GPP) 2022 guidelines versus GPP3 published in 2015 have important implications for publishing industry-funded biomedical research in the region. METHODS: This manuscript provides practical guidance for stakeholders in APAC on interpreting and applying the recommendations made in the GPP 2022 guidelines. RESULTS: Key focus areas include navigating new opportunities for communicating industry-funded research, such as plain language summaries, social media, and preprints; implementing formal processes to improve the integrity of published research in APAC; and methods of promoting transparency and inclusion when publishing industry-funded research. Key APAC-specific issues, including encore presentations, leadership on publication ethics in the region, access to professional resources, and support for educating regional stakeholders are also discussed. CONCLUSIONS: Overall, this manuscript offers a pragmatic guide for stakeholders in industry-sponsored research on applying GPP 2022 in practice with a focus on effectively integrating these guidelines in an APAC context.
Subject(s)
Authorship , Biomedical Research , Humans , Asia , Drug IndustryABSTRACT
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].
ABSTRACT
Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.
ABSTRACT
Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.
Subject(s)
Indolizines/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Administration, Oral , Animals , CHO Cells , Cricetinae , Cricetulus , Dermatitis, Contact/drug therapy , Disease Models, Animal , Drug Evaluation, Preclinical , Eosinophils/drug effects , Eosinophils/metabolism , Half-Life , Humans , Hypersensitivity/drug therapy , Indolizines/pharmacokinetics , Indolizines/therapeutic use , Mice , Mice, Inbred BALB C , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/genetics , Receptors, Prostaglandin/metabolism , Structure-Activity Relationship , Th2 Cells/immunology , Th2 Cells/metabolismABSTRACT
High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.
Subject(s)
Acetates/chemistry , Anti-Inflammatory Agents/chemistry , Pyridines/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Administration, Oral , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Eosinophils/drug effects , Eosinophils/immunology , Humans , Microsomes, Liver/metabolism , Permeability , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.
Subject(s)
Acetates/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Animals , Biological Availability , Eosinophils/drug effects , Humans , Rats , Structure-Activity RelationshipABSTRACT
The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II and in vitro inhibitory value for PBMC proliferation are discussed.