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• W2885322414 abstract "A successful lead optimization campaign requires a careful balance of numerous properties. Essentially, these are the integration of “on-target” effects driving efficacy with appropriate drug disposition characteristics, leading to an acceptable dose and a complementary “on-target” or “off-target” profile that minimizes safety concerns. This chapter illustrates these principles using a case study of a campaign seeking small molecule S1P1 agonist compounds. Early attention to cardiovascular safety was required to mitigate “off-target” S1P3-mediated heart rate decrease. A low projected human dose was desirable to minimize the overall body burden and mitigate safety-related attrition in development with the strategy to focus lead optimization on dose described. The main focus of the case study is a finding during early rodent in vivo safety studies of substantial upregulation of genes encoded by the aryl hydrocarbon receptor (AhR). A brief introduction to AhR biology is provided in the context of drug development with emphasis on CYP1A enzyme induction. A chronological review of the findings, the consequences, subsequent decisions made, and actions taken by the program team is described. Topics discussed include the complementary use of in vitro and in vivo systems, species selection for safety studies, and strategic changes required in compound design and selection. Medicinal chemistry examples are provided, with subtle structure–activity relationships, illustrating the challenge of identifying molecules with appropriate potency and pharmacokinetic properties without CYP1A induction. Examples of molecule profiles appropriate for progression to preclinical development are presented. This case study highlights the operational practicalities and the scientific and strategic judgments required during an evolving drug discovery program. It illustrates that collaborative working across medicinal chemistry, DMPK, biology, and safety assessment disciplines is essential for success." @default.
• W2885322414 created "2018-08-22" @default.
• W2885322414 creator A5069078200 @default.
• W2885322414 date "2018-08-03" @default.
• W2885322414 modified "2023-10-16" @default.
• W2885322414 title "The Integrated Optimization of Safety and DMPK Properties Enabling Preclinical Development: A Case History with S1P ₁ Agonists" @default.
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• W2885322414 doi "https://doi.org/10.1002/9783527801756.ch22" @default.
• W2885322414 hasPublicationYear "2018" @default.
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