The document discusses various considerations for identifying central nervous system (CNS) drugs, including bioavailability. It defines bioavailability as the amount of drug available in the body to act at the target. Three key points are made: 1) Drugs must reach the CNS target area in sufficient amounts during the appropriate time window to have efficacy, otherwise bioavailability limits efficacy; 2) Molecular properties influence absorption, distribution, metabolism and excretion of drugs, impacting bioavailability; 3) Case studies show how changes in CNS bioavailability and metabolism can impact drug safety and efficacy.

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.