BIOAVAILABILITY – drug available in the body to act at target
Inability to reach target in sufficient amounts during appropriate time window LIMITS opportunity for efficacy – BBB, metabolism, efflux
Caveat: Bioavailability DOES NOT guarantee drug efficacy
STARTING POINT: How does an oral drug get into the CNS?
Quantification LogBB = comparison of brain, plasma concentrations Relative bioavailability %F = [AUC po ] / [AUC iv ] Molecular properties influence how drugs are absorbed, how they are distributed, how they interact with transporters and metabolizing enzymes Absorption Metabolism Tissue Distribution Time [Drug]
Case study: Antihistamine CNS bioavailability changes impact adverse events
First-generation antihistamines characterized by sedative side effects
DIPHENHYDRAMINE FEXOFENADINE Brain penetrant Avoids penetrating CNS Antihistamines lacking sedative properties tend to possess limited CNS bioavailability compared to antihistamines with drowsiness Obradovic T et al. (2007) Pharm Res, 24 , 318-327. Avoids P-glycoprotein efflux P-glycoprotein substrate
Case study: CYP2D6 metabolism alters bioavailability, impacts safety/efficacy
CYP2D6 - major isoform involved in CNS drug metabolism!
Genetic polymorphisms affect CYP2D6 expression, function
CYP2D6 phenotype correlates with disease progression in breast cancer Morphine toxicity risk with UM phenotype; Poor efficacy with PM phenotype CODEINE MORPHINE CYP2D6 “ Ultra-rapid” metabolizer phenotype “ Poor” metabolizer phenotype Increased CYP2D6 function Decreased CYP2D6 function TAMOXIFEN 4-HYDROXY TAMOXIFEN CYP2D6 “ Ultra-rapid” metabolizer phenotype “ Poor” metabolizer phenotype Increased CYP2D6 function Decreased CYP2D6 function
Bioavailability…it’s a big deal! So, what can you do to find compounds that are bioavailable? Hint: you don’t need to do in vivo testing just yet..
Molecular Properties 101: Physical properties influence how drugs interact with the body
Absorption : Will the drug penetrate across the GI tract to the circulatory system? Distribution : Will the drug remain soluble in the blood? Will it remain bound to plasma proteins? Metabolism : Will the drug be chemically modified by CYPs? How much will be available to get to the target? Excretion : How will the body eliminate the drug? *Modifying one property has consequences on others Figure modified from van de Waterbeemd H. (2009) Chem Biodiv, 6 , 1760-1766. SOLUBILITY Charge Ionization Dissolution LIPOPHILICITY SIZE H-Bonding Shape Amphiphilicity Charge Distribution LogP MW PSA
Improving the odds: Using properties guidelines can increase bioavailability odds
“ Rule of 5” - Christopher Lipinski
Poor absorption/permeation MORE LIKELY if:
>5 Hydrogen bond donor atoms (HBD)
MW > 500
LogP > 5
N + O > 10
1990s: analyses used to identify ways to improve attrition due to poor bioavailability
Today = Smarter screening platforms
CAVEAT: The Ro5 is NOT CNS specific! Gleevec (imatinib) LogP 2.89 MW 493.6 PSA 86.28 HBD = 8 N + O = 8 Norvir (ritonavir) LogP 2.33 MW 720.6 PSA 202.26 HBD = 11 N + O = 11
What molecular properties are most relevant to CNS?
LogP – lipophilicity, solubility in octanol/H 2 O
MW – size
PSA – polar surface area (N’s, O’s)
How do I calculate these?
Protocols – “ home grown ”
In silico – calculate estimated values derived from real structures
*Discounts available for academics
DISCOVERY TIP: Prior to purchasing or screening libraries – look at the property landscape. How much is CNS relevant?
CNS drug discovery properties analysis – what are “ good ” values?
CNS drugs occupy a more restricted molecular properties space
Properties guidelines also depend on development status (hit versus lead versus drug)
Rees et al. (2004) Nat Rev Drug Discov, 3, 660-672. Lipinski CA et al. (2001) Adv Drug Deliv Rev, 46, 3-26. CNS Drugs LogP < 4 MW < 400 PSA < 80 Chico et al. (2009) Nature Rev Drug Discov , 8, 892-909. Fragments LogP < 3 MW < 300 PSA < 90 Oral Drugs LogP < 5 MW < 500 PSA < 140
Case Study: CNS properties analysis identifies guidelines Properties were computed using ACD Labs (v.11). Data shown are mean±SEM. Student’s t-test used to compare mean values with CNS means. *, p <0.05; ***, p <0.001. Chico et al. (2009) Nature Rev Drug Discov , 8, 892-909. PSA discriminates CNS+ better than LogP Pgp+ compounds possess higher LogP, MW than Pgp- compounds
Case study: Properties guidelines help prioritize CNS drug discovery efforts Simple properties filters helped prioritize the top 6% of candidates! <100 compounds were synthesized from start lead clinical candidate. Wing et al. (2006) Curr Alz Res, 3, 205-214. Chico et al. (2009) Drug Metab Dispos, 37, 2204-11. Chico et al. (2009) Nature Rev Drug Discov, 8 , 892-909. 5 amines + 18 alkyl/aromatic groups = 1700+ possibilities PSA <80Å 2 MW <400 LogP < 4 (80%) (80%) (80%)
Case study: Overlapping properties analyses focuses discovery efforts
Most property analyses focus on one outcome or endpoint…
… but CNS bioavailability involves multiple outcomes (penetration, metabolism for example).
CNS+/CYP2D6- = good!
CNS+/CYP2D6+ = bad!
Future direction of the field – perform properties analysis on multiple outcomes and “overlap” results
Query: where are we most likely to find compounds that are both CNS+ AND CYP2D6-?
Approach: Superimpose properties to find “hotspots” associated with CNS+/CYP2D6- candidates
Chico et al. (2009) Drug Metab Dispos, 37 , 2204-11. Chico et al. (2009) Nature Rev Drug Discov, 8 , 892-909.
Find the “sweet spot” of CNS+/CYP2D6- using overlapping analyses CNS+/CYP2D6+ Avoid this region CNS+/CYP2D6- Minimized risk of CYP2D6 involvement, but still have CNS+ CNS+ PSA ≤ 80Å 2 LogP ≤ 4 MW ≤ 400 Database summary statistics:
Multidimensional properties analyses helps refine “CNS” space Wager et al. (2010) ACS Chem Neurosci, 1 , 420-434. Wager et al. (2010) ACS Chem Neurosci, 1, 435-449 Analyzing properties associated with multiple ADME features helps identify more restrictive guidelines, increases probability of finding CNS+ compounds.
Takeaways – how can I use properties guidelines in my discovery efforts?
Properties can help you focus screening on most “CNS”-relevant members.
Some libraries are more CNS friendly than others.
It is easier to add than subtract later!
Start low – expect to increase as you proceed
Applying guidelines allows chemists to budget their selections
Guidelines are guidelines – NOT rules
Don’t get tripped up by numbers. Rationale trumps rules!!