An Integrated Approach To Drug Discovery Using Parallel Synthesis. The history of parallel chemistry for lead discovery at Pfizer Sandwich from begining to outsourcing

1. An integrated approach to drug discovery using parallel synthesis Graham F Smith Sandwich Chemistry Pfizer Global Research and Development

2. Overview Enabled Hit Follow Up & Productive lead Discovery File Enrichment Chemo informatics High Throughput Chemistry HTS

6. Beautiful compound concept parallel chemistry no toxicophores rule of 5 compliant pure and stable Pfizer exclusive Lipinski, C.A. Chris Lipinski Discusses Life and Chemistry after the Rule of Five. Drug Discovery Today 2003 , 8 , 12-16.

11. File Enrichment – managing diversity La Jolla Groton Ann Arbor Sandwich Generation of ideas for library protocols Global Ideas overlap resolution La Jolla Groton Ann Arbor Sandwich Prioritization of ideas for development Library chemistry development Library idea Management Tool La Jolla Library production and purification

13. Overview Enabled Hit Follow Up & Productive lead Discovery File Enrichment Chemo informatics High Throughput Chemistry HTS

17. Pipeline Pilot tree HTS Actives HTS Hits

18. HTS library output multiple lead options for most targets

19. Global Protocol database intranet access All Parallel Chemistry searchable in one place All 9 PGRD site use this tool All File enrichment research captured in the global database A link from compound to parallel synthesis protocol

20. Architecture based on Formal Reactions Protocols are associated into Formal Reactions VRXN-2-00001 Reductive amination as a family of protocols aldehydes nucleophilic amines Two protocols of broadest scope cover the largest range of potential ---- thus potential for re-use: Capturing these is what really builds the asset in global Chemical Knowledge Bases VRXN-2-00001 is defined by the Formal Reaction scheme and spans the space covered by all suitable amines & aldehydes in the linked inventory db

21. Formal Reactions as Families of Protocols 21 VRXN-3-00029 4 VRXN-3-00007 2 VRXN-2-00081 3 VRXN-2-00018 7 VRXN-2-00017 9 VRXN-2-00016 8 VRXN-2-00013 15 VRXN-2-00011 39 VRXN-2-00010 12 VRXN-2-00009 9 VRXN-2-00007 16 VRXN-2-00005 4 VRXN-2-00004 11 VRXN-2-00002 13 VRXN-2-00001 Source (each color represents one of the Pfizer R&D sites) # of explicit protocols within reaction family Name of Formal Reaction (broad scope rxns)

23. PGVL Hub on the Chemist’s Desktop

24. Access to virtual libraries from the desktop Suitable monomers retrieved for each reaction protocol Properties calculated Inventory and location searched Clustering and filtering pre and post enumeration

25. Spotfire Design analysis

26. Overview Enabled Hit Follow Up & Productive lead Discovery File Enrichment Chemo informatics High Throughput Chemistry HTS

31. Overview Enabled Hit Follow Up & Productive lead Discovery File Enrichment Chemo informatics High Throughput Chemistry HTS

33. The Hardware – 1st generation 6 x 2M Tecan Genesis 8 x Waters LCMS+ELSD 2 x Bohdan Weighing Stations 12 x Gilson 215 based HPLC systems

34. Assorted plate types

35. Assorted plate types continued

36. Tecan Genesis with Argon Blanketing

37. Prep HPLC stacking to save space

38. Barcode based fraction tracking

39. Crystal Structure of UK-411,930 bound to CDK2 - SBLD 2.3A resolution data SRS, Daresbury. Key pyrazole Donor Acceptor Donor interaction

41. Overview of Closed-loops for IKK Activity goes up with library iteration Number of actives increases with library iteration 0 10 20 30 40 50 60 0 1 2 3 4 5&6 Closed-loop iteration % of compounds active at 10  M 1 10 100 1000 10000 activity of most potent compound (nM)

44. PDE5 Library lead: UK-469,413 12-24 hours 18, ER<1 1.9, 3.3 367 32v6, 5v10, 5v11 71nM UK-469413 >12 hours Pred. Hu T1/2 >10, ER<1 Caco abs. 1-2, <3 LogD, LogP <400 MWt >10x vs PDE’s Selectivity  50nM PDE5 IC50 Lead Target Criteria

46. Profiles of selective PDE5 leads Criteria PDE5 IC50 PDE6 Sel. PDE11 Caco2 TPSA N,O count Lead 2 0.80nM 42x 10x 18, ER 1 93 9 Lead 3 0.50nM 104x 160x 2, ER>10 122 11 Great pharmacology, but… efflux problems.

53. Maraviroc - Faster to CAN with parallel synthesis UK-107,543 (HTS hit) 400 nM CCR5 blocker no antiviral activity CYP450 inhibitor UK-427,857 antiviral IC 90 1 nM selective no CYP450 inhibition jun00 dec97 Dorr et al , Antimicrob Agents Chemother ., 2005 , 49 , 11 Armour & Wood, Progress in Medicinal Chemistry , 2005 , 43 , 239, WO2003084954 965 analogues

57. Overview Enabled Hit Follow Up & Productive lead Discovery File Enrichment Chemo informatics High Throughput Chemistry HTS

64. The Attrition Curve 1 2 3 4 5 >12 years 60% 25% Ideas  Leads  Dev. Candidates  PhIIa Clin.  Products 25% 100 Projects 1 Product % Projects 25%