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Combinatorial Chemistry-Parallel Synthesis 1. Introduction: the Drug Discovery Process Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis Agenda 1. Introduction: The Drug Discovery Process 2. Lead Discovery and Lead Optimization-Drugability -Drug-like molecules-the rule of 5 -Drug-like vs lead-like: the rule of 3 -Privileged scaffolds -Unwanted properties: frequent hitters-aggregate forming molecules 3. Combinatorial and Parallel Synthesis in Medicinal Chemistry -Historical background-objective -Compound mixtures versus single compounds -Solid phase synthesis versus synthesis in solution 4. Combinatorial Synthesis of Biopolymers -Polypeptides -Peptoids, Oligoureas, Oligocarbamates -Oligosaccharides -Oligonucletides, Oligonucleosides winter semester 09 Daniel Obrecht, Polyphor Ltd 1 Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis Agenda 4. Combinatorial synthesis of Biopolymers (cont.) -Combinatorial synthesis-split-mixed synthesis -Tagging strategies 5. Strategies for the Synthesis of Small Molecule Libraries -Library synthesis planning -Synthesis strategies -Classical multi-component reactions (MCR’s) -Sequential multi-component reactions (SMCR’s) -Fragment-based lead discovery -Dynamic Combinatorial Synthesis; Target-guided synthesis (TGS) -Disulfide thethering -Click chemistry -Building blocks -Parallel and/or combinatorial synthesis -Parallel work-up winter semester 09 Daniel Obrecht, Polyphor Ltd 2 Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis Agenda 6. Applications of Parallel Synthesis and Combinatorial Chemistry in Medicinal Chemistry: Case Studies -Drug targets 7. Appendix (Definitions; Reviews; Literature) winter semester 09 Daniel Obrecht, Polyphor Ltd 3 Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process The value added chain of pharmaceutical R & D -From 1960 to 1980 the development time of a new NCE (new chemical entity) have quadrupled -Since 1980 9-13 years have been necessary for the louching of a new drug -Costs have gone up from 300-450 MioSFr (1987) to 600-800MioSFr in 2000 -Main reasons: higher degree of scientific knowledge of the drug required; regulations for clinical quality assurance; change in the professional regulations of physicians; increase for administrative work for health authorities -It is of prime importance to reduce the development time and costs for the development of a new NCE in order to reduce the costs of new drugs while keeping the profitability: increase productivity of R & D J. Kuhlmann, Int. J. Clinical Pharmacol. Ther. 1997, 35, 541-552 winter semester 09 Daniel Obrecht, Polyphor Ltd 4 Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process Drug Discovery Process Assay Screening Parallel Medicinal development libraries chemistry chemistry capabilities Establishing Hit Preclinical Hit Lead Target primary exploration, and clinical identification identification optimization screening hit-to-lead development Screening PEM, small Molecular ADMET capabilities molecules, modeling properties fragments Genomics; Proteomics; Phage display, Fragment screening; X-ray crystallography winter semester 09 Daniel Obrecht, Polyphor Ltd 5 Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process Lead Clinical Candidate Selection Optimisation (CCS) from alternatives (Candidate Profiling) Of 10 projects 5-12 m 12-36 months 3-6 m starting in Lead Identification Attrition in Discovery <3.5 will reach 1 2 . 0 0 >30% 1 0 . 0 0 CCS (..but 8 . 0 0 30% >50% 5 6 . 0 0 30% possible?) 4 . 0 0 2 . 0 0 0 . 0 0 Lead Identification Lead Optimisation CCS Selecting Leads that Removing Selecting the candidate that provides are “drugable” the ADMET the best exposure (e.g. unbound Avoiding problematic concerns concentration at target ) without templates safety concerns winter semester 09 Daniel Obrecht, Polyphor Ltd 6 Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process Phase 1 Phase 2 Phase 3 Regulatory Proof-of- Efficacy Approval Concept Long term Safety 6-9 m 12m 12-24m 24m 12-24m Attrition in Development 30% 1 6 . 0 0 1 4 . 0 0 10% 40%* EIH Enabling 1 2 . 0 0 20% P h a s e 1 1 0 . 0 0 62%* P h a s e 2 8 . 0 0 50% P h a s e 3 6 . 0 0 45%* 13%* Registration 4 . 0 0 20% NDA 2 . 0 0 <5% 0 . 0 0 4% of EIH Enabling Ph a s e 1 P h a s e 2 Ph a s e 3 Registration NDA marketed cpds withdrawn Ensuring PK, metabolism, exposure, Long term pre-clinical & clinical safety, half-life,, safety, in humans are as carcinogenicity studies. expected. Definition of possible human Final assessment of drug-drug interactions & safety issues and margins. of bioavailability of the final marketed Reproductive toxicity formulation winter semester 09 Daniel Obrecht, Polyphor Ltd 7 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process Brain Various Tissues Dose Metabolism and biliary clearance of Metabolism Tissue unchanged drug Dissolution distribution Systemic Circulation Liver Metabolism and exhalation Gut Wall pH ranges by lung Gut stomach 1.5-6 upper g.i. tract Portal Lumen pH 4.4-7.8 Permeation colon 5 Vein effect of food, bile acids etc Metabolism Renal excretion of drug Undissolved and/or metabolites dose winter semester 09 Daniel Obrecht, Polyphor Ltd 8 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process winter semester 09 Daniel Obrecht, Polyphor Ltd 9 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process winter semester 09 Daniel Obrecht, Polyphor Ltd 10 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process winter semester 09 Daniel Obrecht, Polyphor Ltd 11 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process Absorption Conc vs Time Curves phase 12 t max Cmax 10 Distribution & Elimination 8 Phase L / g 6 m C 4 -1 t ½ = 6h, k =0.693/t1/2= 0.12h 2 Cmin 0 0 5 10 15 20 25 30 Time (h) C mg/L_Oral C mg/L_IV winter semester 09 Daniel Obrecht, Polyphor Ltd 12 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 1. Introduction: The Drug Discovery Process bioavailability of drugs Plasma concentration Drug injected AUC (oral) Bioavailability = AUC (injected) AUC Drug given orally (injected) AUC (oral) Time winter semester 09 Daniel Obrecht, Polyphor Ltd 13 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 2. Lead Discovery and Lead Optimization-Drugability Drug-like molecules-the rule of 5 What is a drug-like molecule? leading references: [1] C. Lipinsky et al. Adv. Drug Delivery Rev. 1997, 23, 2; [2] H. Kubinyi et al. J. Med. Chem. 1998, 41, 3325; [3] M. Murko et al. J. Med. Chem. 1998, 41, 3314; ¨[4] J. R. Proud- food, Bioorg. Med. Chem. Lett. 2002, 12, 1647 linezolid (antibiotic) Lipinski's rules of 5: H-acceptor -logP < 5 -molecular weight < 500 (600) -not more than 5 H-bond donors F O -not more than 10 H-bond acceptors (or 10 hetero atoms) O O H-acceptor O N N -not more than 5 (10) rotatable bonds N H molecules which obey to Lipinski's H-acceptor rule of 5 have a high propensity for penetration into cells and for oral H-donor absorption C15H18FN3O4 (323.33) winter semester 09 Daniel Obrecht, Polyphor Ltd 14 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 2. Lead Discovery and Lead Optimization-Drugability Drug-like molecules-rule of 5 Ac-RGDSNH2 (fibrinogen antagonist) Lipinski's rules of 5: + -logP < 5 - H2N NH2 x Cl -molecular weight < 500 (600) -not more than 5 H-bond donors HN OH -not more than 5 H-bond acceptors O (or 10 hetero atoms) O O O -not more than 5 (10) rotatable bonds H H N N molecules which obey to Lipinski's N N NH2 H H rule of 5 have a high propensity for O O OH penetration into cells and oral absorption C17H30N808 x HCl (511.03) MG: ok; logP < 5 (ok); 13 H-donors (violation); 16 hetero atoms (violation); 17 rotatable bonds (violation) -peptides, proteins, oligonucleotides and oligosaccharides in general show violations of Lipinski's rules; -these molecules have many H-bond donors and acceptors, which in physiological environment are surrounded by water molecules. They show generally low cell penetration, low passage through the blood brain barrier and low oral absorption. In addition these molecules are generally quickly degraded by various enzymes, which can also be an advantage. -these molecules have to be administered by a topical, i.p. or i.v. route; in recent years significant progress has been made in administering biomolecules: liposomes, inhalation methods, direct injection techniques into the brain.. winter semester 09 Daniel Obrecht, Polyphor Ltd 15 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 2. Lead Discovery and Lead Optimization-Drugability privileged fragments NMR based screening of fragments binding towards a variety of proteins: Bcl-2 (an antiapoptotic protein), stromeolysin (MMP), VEGF-RBD, p56lck SH2, FK-506 BP and others. S. W. Fesik et al. J. Med. Chem. 2000, 43, 3443-47 O N OH N N N O N N H OH P OH O winter semester 09 Daniel Obrecht, Polyphor Ltd 16 Medicinal Chemistry : Combinatorial Chemistry-Parallel Synthesis 2. Lead Discovery and Lead Optimization-Drugability Lead-like: the rule of 3 The properties of 40 fragment hits identified against a range of targets using high throughput X-ray crystallographic screening technology has been examined. The results indicated that on average fragment
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