4. Bioavailability…it’s a big deal! So, what can you do to find compounds that are bioavailable? Hint: you don’t need to do in vivo testing just yet..

9. Case Study: CNS properties analysis identifies guidelines Properties were computed using ACD Labs (v.11). Data shown are mean±SEM. Student’s t-test used to compare mean values with CNS means. *, p <0.05; ***, p <0.001. Chico et al. (2009) Nature Rev Drug Discov , 8, 892-909. PSA discriminates CNS+ better than LogP Pgp+ compounds possess higher LogP, MW than Pgp- compounds

10. Case study: Properties guidelines help prioritize CNS drug discovery efforts Simple properties filters helped prioritize the top 6% of candidates! <100 compounds were synthesized from start  lead  clinical candidate. Wing et al. (2006) Curr Alz Res, 3, 205-214. Chico et al. (2009) Drug Metab Dispos, 37, 2204-11. Chico et al. (2009) Nature Rev Drug Discov, 8 , 892-909. 5 amines + 18 alkyl/aromatic groups = 1700+ possibilities PSA <80Å 2 MW <400 LogP < 4 (80%) (80%) (80%)

12. Find the “sweet spot” of CNS+/CYP2D6- using overlapping analyses CNS+/CYP2D6+ Avoid this region CNS+/CYP2D6- Minimized risk of CYP2D6 involvement, but still have CNS+ CNS+ PSA ≤ 80Å 2 LogP ≤ 4 MW ≤ 400 Database summary statistics:

13. Multidimensional properties analyses helps refine “CNS” space Wager et al. (2010) ACS Chem Neurosci, 1 , 420-434. Wager et al. (2010) ACS Chem Neurosci, 1, 435-449 Analyzing properties associated with multiple ADME features helps identify more restrictive guidelines, increases probability of finding CNS+ compounds.

15. Thank you for your time

16. Synthetic Chemistry Essentials for Biologists February 2012 Heather Behanna, PhD Biotechnology Research Associate [email_address] (312) 768-1795

18. http://www.sciencecartoonsplus.com/pages/contact.php

19. An overview of the drug discovery process Nature Review Drug Discovery,8, 892 2009.

20. The Drug Discovery Chemist Synthetic chemistry- How to make things Medicinal chemistry- What makes a drug Pattern recognition and recall

21. Pattern recognition and recall TNT Salinsporamide – clinical trials for cancer Point of covalent attachment to proteins Azo-blue

22. Chemical space versus drug-like space Lipinski, C and Hopkins A, Nature , 2004 , 432(16) 855. Nature Biotechnology 24, 805 - 815 (2006)

25. An overview of the drug discovery process Looking for a starting point – either binding or weak activity that can then be optimized Obtainment of a Hit

28. HTS pitfalls - Bad Hits and Frequent Hitters J Chem Inf Model. 2007 Jul-Aug;47(4):1319-27. Pattern recognition and recall Compounds that are potent in HTS are not necessarily Hits!

31. How can we do that?

33. An overview of the drug discovery process “ Hit to Lead” Nature Review Drug Discovery,8, 892 2009.