Bioavailability: An Agrochemical Research Perspective

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 AgrochemicalsPotency 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
Bioavailability Foliar Application
5
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 stability poor we have a problem
  lead.
• when mobility AND stability poor the nightmare
  begins!
• dream leads have a balanced potency-mobility-stab
  ility profile.
• avoid the nightmares address the problems,
  define the balance.

7
Defining the BalancePotency-Mobility-Stability
Profiles

• Understand profiles for effective compounds to
  enable definition of profile options 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 (15 cm) physically
  coated with octanol aqueous octanol saturated
  mobile phase _at_ 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 _at_ 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 ais)
11
Measured vs Predicted PropertiesAqueous
Solubility (Sw ppm ?g/ml) (50 ais)
12
LogP (Octanol), (Hexane), (?logP) CHI Measured
data examples (50 ais)
13
Agrochemical Products Properties Pesticide
Manual 11th Ed. 1997

• Molecular weight
• 200 to 500 range (86) lt 200 (11) gt 500 (3)
• Melting point (C)
• 50 to 200 range (60) lt 50 (30) gt 200 (10)
• pKa (acid)
• 10 compounds with pKa lt 5
• pKa (base)
• 1 compounds with pKa gt 5

14
Agrochemical Products logP ProfilePesticide
Manual 11th Ed. 1997 (500 ais)
15
Agrochemical Products logSw (ppm)
ProfilePesticide Manual 11th Ed. 1997 (500 ais)
16
Effective Agrochemicals LogP Profile (3000
ais)
Octan-1-ol
25
Absolv
20
ClogP3
ClogP4
15

10
5
0
lt-8
-7
-5
-3
-1
1
3
5
7
9
gt10
gtx
17
Effective Agrochemicals Property Profiles
(3000 ais)
18
Drug Design BioavailabilityLipinskis Rule of
5

• Poor adsorption/permeation likely for structures
  where 2 or more of these limits exceeded.
• LogP octanol lt 5 (via CLOGP)
• Molecular weight lt 500
• H-Bond Donors lt 5 (sum of OH NHs)
• H-Bond Acceptors lt10 (sum of N Os)
• 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 lt300 C
• H-Bond Donors ? 3 (sum OH NHs)
• Delta logP lt3 (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 BioavailabilityTices 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 Lipinskis Rule of 5 for pharmaceuticals
  apply to agrochemicals

21
Agrochemical Design BioavailabilityClarke-Delane
y Guide of 2

• Suggest gt 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 OHs NHs)
• Stability Alerts ? 2
• (EDC/JD March 2000)