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Bioavailability: An Agrochemical Research Perspective

Bioavailability: An Agrochemical Research Perspective. Eric Clarke. Acknowledgements.

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Bioavailability: An Agrochemical Research Perspective

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  1. Bioavailability: An Agrochemical Research Perspective Eric Clarke

  2. Acknowledgements • Syngenta: Chemistry Design GroupDavid Adams, John Delaney, Torquil Fraser, Patrick Gardinal, Kevin Lawson, Graham Mullier, Andy Pierce, Tony Seville, Beth Shirley, Graham Sexton, Gail Templeman, Francesco Vallorani, Russell Viner • UCL ‘Abraham Research Group’ (LSER)Mike Abraham, Kei Enomoto, Jamie Platts (Cardiff Univ) , Caroline Green (Pfizer) • GlaxoSmithKline (CHI; logD/logP, pKa; solubility) Derek Reynolds, Chris Bevan, Klara Valko, Alan Hill • Sirius Analytical Instruments (GLpKa/D-PAS; Absolv)John Comer, Colin Peake, Karl Box, Lynne Trowbridge, Stephen Pouros • AstraZeneca (logD/logP; pKa; solubility) Nicola Colclough, Alan Wait, Brian Law

  3. Bioefficacy of Agrochemicals‘Potency – Mobility – Stability’ Balance • Factors influencing balance: • Wide variety of very different target organisms • weeds, fungi, insects • Range of application modes • soil & foliar applied herbicides • protectant, eradicant & systemic fungicides • contact, residual and soil applied insecticides • Variable environmental conditions • climate, location

  4. UPTAKE INTO AND TRANSLAMINAR MOVEMENT IN UPTAKE INTO AND PLANT MOVEMENT IN INSECT HYDROLYSIS AND HYDROLYSIS AND METABOLISM IN METABOLISM IN PLANT INSECT R A I N W A S H V O L A T I L I S A T I O N PHLOEM MOVEMENT - PHOTODEGRADATION LEAVES TO ROOTS GREEN = TRANSPORT PROCESS RED = LOSS PROCESS B O T H = C O M B I N A T I O N Bioavailability – Foliar Application

  5. UPTAKE INTO AND MOVEMENT IN INSECT HYDROLYSIS AND METABOLISM IN PLANT HYDROLYSIS & METABOLISM XYLEM MOVEMENT - IN INSECT V O L A T I L I S A T I O N ROOTS TO LEAVES PHOTODEGRADATION RELEASE GREEN = TRANSPORT DIFFUSION MOVEMENT INTO SOIL RED = LOSS BINDING ROOT UPTAKE B O T H = C O M B I N A T I O N DEGRADATION LEACHING Bioavailability: Soil Application

  6. Bioavailability of AgrochemicalsLead ‘Potency-Mobility-Stability’ Balance • potent in vitro leads need to be available in vivo to express activity & spectrum. • bioavailability depends both on mobility & stability. • when mobility OR stabilitypoor we have a problem lead. • when mobility ANDstability poor the nightmare begins! • dream leads have a balanced‘potency-mobility-stability’ profile. • avoid the nightmares; address the problems,define thebalance.

  7. Defining the Balance‘Potency-Mobility-Stability’ Profiles • Understand profiles for effective compounds to enable definition of profileoptions for leads: • commercial products • development compounds • evaluation compounds • Profile compounds of diverse molecular properties, moa, spectrum, application rate & time course of action: • HTS  Glasshouse  Field

  8. Agrochemicals: Physical PropertiesBioavailability Related Parameters • Mobility related (~500/yr  ~500/mth  ~500/wk) • Organic/water partition (logD/logP oct; Log P, delta logP ) • Acid/base dissociation (pKa) • Aqueous & organic solvent solubilities • Volatility (WindTunnel; deposit on glass) • Stability related (~500/yr) • Hydrolysis (water/esterase) • Thiol reactivity (GSH/GST) • Oxidative stability (oxidant/porphyrin) • Photostability (SunTest; deposit on glass/solution)

  9. Agrochemicals: Mobility PropertiesLogP (Oct) & Aqueous Solubility: Methods • Octanol/water partition (logD/logP) • HPLC(C8/18) hybrid columns (1–5 cm) physically coated with octanol; aqueous octanol saturated mobile phase @ pH 7 (optional pH 2 to 9); logD proportional R; related to standards; range 1 to 4 routine; 0 to 5 possible • Aqueous solubility (logSw) • Ultrasonic dispersion (1 hr) +/- roller shaking (16 hrs)sample (1 mg/ml) in aqueous buffer @ pH 7 (pH 2 to 9)centrifuged/filtered prior to analysis (RP-HPLC)range 0.1 to 1000 ppm (ug/ml)

  10. Measured vs Predicted PropertiesLogP (octanol) examples (~50 ai’s)

  11. Measured vs Predicted PropertiesAqueous Solubility (Sw; ppm = g/ml) (~50 ai’s)

  12. LogP (Octanol), (Hexane), (logP) & CHIMeasured data examples (~50 ai’s)

  13. Agrochemical Products: Properties Pesticide Manual 11th Ed. 1997 • Molecular weight • 200 to 500 range (86%); < 200 (11%); > 500 (3%) • Melting point (°C) • 50 to 200 range (60%); < 50 (30%); > 200 (10%) • pKa (acid) • ~10% compounds with pKa < 5 • pKa (base) • ~1% compounds with pKa > 5

  14. Agrochemical Products: logP ProfilePesticide Manual 11th Ed. 1997 (~500 ai’s)

  15. Agrochemical Products: logSw (ppm) ProfilePesticide Manual 11th Ed. 1997 (~500 ai’s)

  16. ‘Effective’ Agrochemicals: LogP Profile (~3000 ai’s) Octan-1-ol 25 Absolv 20 ClogP3 ClogP4 15 % 10 5 0 <-8 -7 -5 -3 -1 1 3 5 7 9 >10 >x

  17. ‘Effective’ Agrochemicals: Property Profiles (~3000 ai’s)

  18. Drug Design: BioavailabilityLipinski’s Rule of ‘5’ • Poor adsorption/permeation likely for structures where 2 or more of these ‘limits’ exceeded. • LogP octanol < 5 (via CLOGP) • Molecular weight < 500 • H-Bond Donors < 5 (sum of OH & NH’s) • H-Bond Acceptors <10 (sum of N & O’s) C. A. Lipinski, F. Lombardo, B. W. Dominy, P.J. Feeney Advanced Drug Delivery Reviews, (1997), 23, 3-25 ‘Experimental & computational approaches to estimate solubility & permeability in drug discovery & development settings’

  19. Agrochemical Design: BioavailabilityBriggs Rule of ‘3’ • bioavailability likely to be poor for structures where 3 or more of these ‘limits’ exceeded: • logP octanol  ~3 • Molecular weight ~300 • Melting point <300 C • H-Bond Donors  3 (sum OH & NH’s) • Delta logP <3 (logP oct - logP alk) G. G. Briggs, Agrevo UK SCI Meeting, Dec 1997, Uptake of Agrochemicals & Pharmaceuticals ‘Predicting uptake & movement of agrochemicals from physical properties’

  20. Agrochemical Design: BioavailabilityTice’s Rules • Insecticidal (I) or post-emergence herbicidal (H) activity more likely when: • logP octanol (mlogP)  3.5(H) 0 &  5(I) (alogP)  5.0(H) 0 &  6.5(I) • Molecular Weight 150 &  500 (I & H) • H-Bond Donors  3 (H)  2 (I) • H-Bond Acceptors  2 &  12(H)  1 &  8(I) C. M. Tice; Pest Management Science, 2001, 57, 3-16 ‘Selecting the right compounds for screening: does Lipinski’s Rule of 5 for pharmaceuticals apply to agrochemicals

  21. Agrochemical Design: BioavailabilityClarke-Delaney Guide of ‘2’ • Suggest > probability of lead progression when: • Molecular weight 200 - 400 • Melting point (deg C)  200 • LogP oct  4 (via 2 methods for estimation) •  LogP  2 (logP oct - logP alk) • pKa (base) 7 +  2 (-  2 for herbicides) • LogSw 2 +/- 1 (10 -1000 ppm) • H-Bond Donors  2 (sum OH’s & NH’s) • Stability Alerts  2 (EDC/JD March 2000)

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