Advertisement

Discovery and Preclinical Work

  • Daria Mochly-RosenEmail author
  • Kevin Grimes
Chapter
Part of the SpringerBriefs in Pharmaceutical Science & Drug Development book series (BRIEFSPSDD)

Abstract

In any drug discovery and development effort, we must accomplish a number of critical steps to arrive at a compound that is safe and efficacious, and also exhibits the complex array of desired drug-like behaviors that warrants advancement to the clinic. These tasks include target identification and validation; screening for active compounds; chemical modification of candidate compounds to achieve optimized pharmacology; formulating the final drug product; and establishing safety in preclinical models. “Repurposing” drugs that have previously been approved (or shown to be safe in humans) for new clinical indications can provide a faster, less risky, and more cost-effective route for bringing a new therapy to patients. Such shortcuts in development can be particularly valuable to resource-constrained academicians. When performing drug discovery research, we must be particularly attentive to the robustness of our experiments, because inability to reproduce academic data continues to be a sticking point when projects are transferred to industry. Our experiments must be appropriately blinded, statistically powered, and meticulously documented so that our findings are worthy of the large investment required for their further translation into a drug. This chapter walks through the essential preclinical drug development steps that lead to a clinical drug candidate.

Keywords

Active Pharmaceutical Ingredient Lead Optimization ADME Property Secondary Assay Preclinical Safety Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Begley CG, Ellis LM (2012) Raising standards for preclinical cancer research. Nature 483:531–533PubMedCrossRefGoogle Scholar
  2. 2.
    Prinz F, Schlange T, Asadullah K (2011) Believe it or not: how much can we rely on published data on potential drug target? Nat Rev Drug Discov 10:328–329CrossRefGoogle Scholar
  3. 3.
    King C, Sarvetnick N (2011) The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions. PLoS ONE 6:e17049PubMedCrossRefGoogle Scholar
  4. 4.
    Begley CG (2013) Six red flags for suspect work. Nature 497:433–434PubMedCrossRefGoogle Scholar
  5. 5.
    Peers IS, Ceuppens PR, Harborn C (2012) In search of preclinical robustness. Nat Rev Drug Discov 11:733–734PubMedCrossRefGoogle Scholar
  6. 6.
    Kneller R (2010) The importance of new companies for drug discovery: origins of a decade of new drugs. Nat Rev Drug Discov 9:867–882PubMedCrossRefGoogle Scholar
  7. 7.
    Code of federal regulations, title 21 food and drugs, subchapter D drugs for human use, part 312, subpart B investigational new drug application, 312.2Google Scholar
  8. 8.
    Huang R, Southall N, Wang Y et al (2011) The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Sci Transl Med 3:80ps16PubMedCrossRefGoogle Scholar
  9. 9.
    Collins FS (2011) Reengineering translational science: the time is right. Sci Transl Med 3:90cm17PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang JH, Chung TDY, Oldenburg KR (1999) A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 4:67–73PubMedCrossRefGoogle Scholar
  11. 11.
    Copeland RA (2003) Mechanistic considerations in high-throughput screening. Anal Biochem 320:1–12PubMedCrossRefGoogle Scholar
  12. 12.
    Wu G, Yuan Y, Hodge CN (2003) Determining appropriate substrate conversion for enzymatic assays in high-throughput screening. J Biomol Screen 8(6):694–700PubMedCrossRefGoogle Scholar
  13. 13.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 23:3–25CrossRefGoogle Scholar
  14. 14.
    Rydzewski RM (2008) Real world drug discovery: a chemist’s guide to biotech and pharmaceutical research. Elsevier Science, Oxford,  Chapter 9 Google Scholar
  15. 15.
    Ekroos M, Sjogren T (2006) Structural basis for ligand promiscuity in cytochrome P450 3A4. PNAS 103:13682–13687PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Chemical and Systems BiologyStanford University School of MedicineStanfordUSA
  2. 2.Chemical and Systems BiologyStanford University School of MedicineStanfordUSA

Personalised recommendations