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MEDICINAL CHEMISTRY: from HIT to LEAD CCTS Drug Discovery Seminar Series May 4, 2018 Corinne E

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MEDICINAL CHEMISTRY: from HIT to LEAD CCTS Drug Discovery Seminar Series May 4, 2018 Corinne E MEDICINAL CHEMISTRY: FROM HIT TO LEAD CCTS Drug Discovery Seminar Series May 4, 2018 Corinne E. Augelli-Szafran, Ph.D. Director, Chemistry Department Southern Research Drug Discovery | 1 Drug Discovery Pipeline Bench………….to………….Bedside Some facts: • 10% of the compounds make it to preclinical development • 70% of these compounds make it to Phase 1 • 20% of Phase 1 compounds make it to market • Odds are < 10% of making it to market • 30% of new drugs return cost of development • 6 yrs from idea to First In Human (FIH) • 8 yrs from FIH to market approval •Total of ~ 12-15 yrs to get to market •$802 MM cost of drug to market -AlzForum.org ~2007 5/4/2018 Southern Research Drug Discovery 2 A Few StepsChallenges to Clinical Trials Clinical Trial In vivo efficacy In vivo toxicity (MTD) Formulation CNS penetration Pharmacokinetic profiling Solubility Hepatocyte stability in mice and human Metabolic stability in mice and human Selectivity Potency Intellectual Property Hit/Lead identification 5/4/2018 Southern Research Drug Discovery 3 What is needed for ‘Hit to Lead’? 1. Identification of Hits/Lead Compounds a. High Throughput Screens (HTS) b. Rational Design / Med chemistry of literature compounds c. Computational Approach d. Structural Biology/Crystal Structure 2. Good Chemical Matter a. Does the compound/chemical series have drug-like properties? b. Can modifications be made to the compound/chemical series to make it drug-like? c. Is the compound or chemical series a dead-end? 5/4/2018 Southern Research Drug Discovery 4 Good Chemical Matter: Guidelines, Tools and Examples • Lead Quality Attributes • Compound profile • Compound Progression Pathway • Med Chem Strategy • Guidelines to Drug-like Properties • Structural alerts • Metabolic stability • Potency, solubility, selectivity, stability 5/4/2018 Southern Research Drug Discovery 5 Lead Quality Attribute Checklist Chemical Series Attributes Met 1 Potency: In vitro potency < 100 nM yes 2 SAR: Evidence of SAR with > 10X change in potency yes 3 Cellular activity / toxicity: Active / no toxicity yes 4 Selectivity yes 5 Safety: No toxicophores or reactive moieties yes Physicochemistry: In vitro ADME studies of similar framework 6 yes show solubility and absorption Synthesis: Synthetic chemistry flexibility is high; 7 yes amenable to rapid, highly productive analog synthesis 8 Intellectual property: Proprietary yes 9 Synthesis: Amenable to parallel synthesis yes 5/4/2018 Southern Research Drug Discovery 6 Compound Profile Physicochemical and Pharmacokinetic Properties DATA TARGETED VALUES Aβ42cells IC50 (nM) < 100 nM Selectivity (Notch Elisacells / Aβ42 Elisacells) > 300 Molecular Weight < 500 Polar Surface Area < 70 Solubility (µM) (In PBS at pH 7.4 (µM)) > 10 µM Experimental Log D 2 - 4 Microsome Stability: Mouse > 20% (or t ½ = 1h) (% remaining @ 60 min) Intrinsic Clearance1 <15 Low Risk; >40 High Risk Microsome Stability: Human > 20% (or t ½ = 1h) (% remaining @ 60 min) Intrinsic Clearance1 <15 Low Risk; >40 High Risk Hepatocyte Stability: Mouse > 20% (or t ½ = 1h) (% remaining @ 120 min) Intrinsic Clearance1 <15 Low Risk; >40 High Risk Hepatocyte Stability: Human > 20% (or t ½ = 1h) (% remaining @ 120 min) Intrinsic Clearance1 <15 Low Risk; >40 High Risk 1 (mL/min/mg/protein) 5/4/2018 Southern Research Drug Discovery 7 Screening Tree – Compound Selection Purifed γ-Secretase Enzyme Assay Aβ40 ELISA + Notch Flag WB New Lead Solubility • Series • Mouse + Human liver microsome stability IC50’s: Aβ42 + Notch Cellular Assays SAR & Lead • Mouse + Human + Cellular Toxicity (MTS) Development hepatocyte stability Active & Interesting • Log D Compounds Microdialysis In vivo Lead Studies Candidates Optimization • PK studies • Brain Neuronal penetration Culture Assay Mouse Studies • P450 enzymes Total Proof compounds • Selectivity panel Efficacious cpds • Toxicity of >1400 Principle 5/4/2018 Southern Research Drug Discovery 8 Medicinal Chemistry Strategy Synthesis of Analogs Test Potency PK Parameters and Selectivity on Leads < 100 nM . IC50 <10 µM; <1 µM . IC50 >10 µM 2- to 3-fold > . (Notch) Selective . Nonselective Avagacestat . Good PK . Poor PK (known drug) Test In Vivo Terminate Series 5/4/2018 Southern Research Drug Discovery 9 Guidelines to Drug-Like Properties STEP 2 / Optimization STEP 1 / Early Stage CNS DRUGS % Bioavailability (30) Rule of 5 Brain Penetration t ½ (> 2h, i.e., BID) Structural ‘alerts’ Clearance Ease of synthesis Smaller is Better (MW = 300) Non-target selectivity profile Solubility (>10 g/mL) µ Log D (2-4) Plasma protein binding Log D (2-4) Polar Surface Area < 70 hERG testing Mouse (Rat) Micr/Hep (>20%) < 5 Total H-Donors or Acceptors P450 interactions (>3 µM) Human Micr/Hep (>20%) < 4 Total Rings, Rotatable Bonds Pgp IC (< 1 M ) 50 µ < 3 Three Aromatic Rings Mini-Ames Minimum effective dose Brain / Plasma (0.5 – 1) POC STEP 3 / Pre-Clinical Development Genetic toxicology In vivo studies / dose response Side-effect profiling Biomarker Defined mechanism of action Differentiation vs. known drugs POC = Proof of Concept 5/4/2018 Southern Research Drug Discovery 10 Structural Alerts • Structural alerts have the potential • A structural alert alone is not for: predictive of an adverse outcome. •Intrinsic reactivity •DNA intercalation • Other factors to consider: •Metal coordination or metabolic activation •Clinical dose (e.g., to a species capable of covalent binding) •Route of drug clearance •This binding could then lead to: •Presence of metabolic routes •Mutagenicity (e.g., that divert metabolism •CYP inhibition away from the structural alert) •Direct toxicity •Carcinogencity •Idiosyncratic toxicity 5/4/2018 Southern Research Drug Discovery 11 Examples of Structural Alerts Potential DNA Damaging Agents Potential Metal Chelators N N N HN A N N N O O O and R Imidazoles Pyridine Triazoles derivatives Amino triazoles Furocoumarins/tricyclics Undergo Metabolic Activation.........or not....... O S N S C H EWG C N O Michael Acceptor Furan Thiophene Pyrrole Thioamides Aldehyde O R2 R1 O N N S X Thiocarbamates C, H S X=H, SR, Acyl S Thiols and Disulfides O OH N N Quinones (Hydroxy)anilines Thioureas 5/4/2018 Southern Research Drug Discovery 12 Metabolism…How to improve? • Avoid structural alert moieties in a molecule • Find replacements (bioisosteres) of particular groups/rings • Block potential sites of metabolism on aryl rings • Use calculations such as CSL (StarDrop) to prioritize analogs with predicted better metabolic stability • CSL (Composite Site Liability) is a measure of the efficiency of metabolism of a molecule by e.g., CYP3A4, one of the CYP isoenzymes. • CSL varies between 0 and 1 (lower values indicate greater metabolic stability) 5/4/2018 Southern Research Drug Discovery 13 Solubility…how to improve? • Add polar or solubilizing groups • OH, N, OR, COOH • Include cycloalkyls containing heteroatoms • Insert heterocycles • Interrupt intramolecular hydrogen bonding • Insert groups that will allow rings to rotate within a molecule….disrupting planarity 5/4/2018 Southern Research Drug Discovery 14 Example of Potency, Stability and Selectivity O O O O O O O S S N S N Resolution OH Br N (R) Br O (S) O Cl O F * O NH NH F F Aβ40 IC50 = 3400 nM Racemate 1st Generation Aβ IC = 120 nM O O 40 50 S N Br 2nd Generation O (R) O NH Aβ40 IC50 = 13 nM open the ring O O F S Potency O O O O N S Stability Cl Selectivity N S O N N Cl (R) O O N O O NH2 N O CF3 NH 2 N NH2 NH CF3 2 •Aβ IC = 113 nM •Aβ IC = 4.1 nM •Aβ40 IC50= 0.3 nM 40 50 40 50 •Notch IC50 = 560 nM (5X) •Notch IC50 = 960 nM (230X) •Notch IC50= 58 nM (190x) •B/P =0.01 (low BBB penetration) BMS-708163 (Avagacestat) •RLM (19%), HLM (44%) @10 min incub 5/4/2018 Southern Research Drug Discovery 15 Example of Potency and Stability Potency O O O O S OH S OH Lead N N Hit H H Cl Cl Aβ40 IC50= 5549 nM Aβ40 IC50= 294 nM Selectivity: 3.7-fold Selectivity: 10-fold Potency Oxidation CF3 CF3 F3C CF3 O O Stability Stability O O S S OH O O S S OH Cl N S S OH Cl N H Cl N H H Glucuronidation Aβ40 IC50= 15 nM Aβ40 IC50= 25 nM Aβ40 IC50= 16 nM Selectivity: 14-fold Selectivity: 15-fold Selectivity: 10-fold •48 min (mice) •24 min (mice) •1 min (mice) •>90 min (human) •8 min (human) •8 min (human) GSI-953 5/4/2018 Southern Research Drug Discovery 16 Identification of Hits/Lead Compounds 1. High Throughput Screens (HTS) 2. Rational Design / Med chemistry of literature compounds 3. Computational Approach 4. Structural Biology/Crystal Structure 5/4/2018 Southern Research Drug Discovery 17 Case Studies - HTS 1.TXNIP – Diabetes 2.LRRK2 – Parkinson’s disease 3.CHIKV (Chikungunya) virus – Antiviral 5/4/2018 Southern Research Drug Discovery 18 Compound Libraries at Southern Research One million small molecules • Chembridge, Enamine, Tripos • Kinase library • 26,734 compounds theoretically designed to inhibit kinases • Approved drugs and biological actives library • 2,500 FDA approved drugs • 460 unapproved drugs • Fragment libraries • Southern Research Proprietary library (34K) • Compounds from SR Research Programs 5/4/2018 Southern Research Drug Discovery 19 1. TXNIP (Thioredoxin Interacting Protein) Goal • Develop a small molecule inhibitor of TXNIP as a novel approach for diabetes therapy Results • 300,000-compound primary screen resulted in 3197 hits • 3197 compounds re-screened for both primary and cytotoxic effects in INS1 cells, resulting in 1258 compounds • 1258 compounds counter-screened for off-target activity resulted in 651 “good” compounds • Focus on 4 series for medicinal chemistry 5/4/2018 Southern Research
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