Hit to Lead and Lead to Drug optimization

Question 1

Hit

Answer 1

A small molecule which exhibits the desired pharmacology towards the target (TDD) or phenotype (PDD)

Question 2

Lead

Answer 2

• Novel structure that exerts disease modifying effects (typically in an animal model) that has a defines SAR and plausible optimisation path towards the drug
• patentable

Question 3

Drug/ candiate

Answer 3

product of the optimisation effort that will be progressed towards clinical and pre-clinical development

Question 4

TPP

Answer 4

Description of the new drug asset and how it addresses an unmet clinical need

Question 5

Drug Selection Matrix

Answer 5

A detailed description (matrix) of the clinical and pre-clinical endpoints that a candidate directed to the TPP must satisfy

Question 6

Drug Assay Cascade

Answer 6

A series of experiments/assays that have been stratified to enable a stage wise progression from a hit to lead and lead to a candidate that fulfils stipulated requirements of the DSM

Question 7

Stage 1

Answer 7

Potency: EC50 < 100 nm

Sel > 50 fold

Log P, D MW, TPSA etc

LE > 0.4

LipE > 4

LELP < 8

Question 8

Stage 2

Answer 8

ADME

1. Solubility Sw > 30 uM
2. Permeability Papp > 4e-6 cm/s
3. Microsomal stab HLM t/12 > 120 mins

Question 9

Stage 3

Answer 9

Toxicokinetics

Rodent PK, Repeat dose tox, cytotoxicity

1. Oral BA > 20% , T1/2 > 4h, Cmax 10xIC50
2. NOAEL > 300 mg/ kg
3. Cytotox > 30 uM

Question 10

Stage 4

Answer 10

1. Efficacy
2. Off target
3. Cyp inhibition
4. Chromosomal Tox
5. Stability studies

Question 11

SAR guided optimization

(w/ functional groups and their issue)

Answer 11

Question 12

Increasing potency

Answer 12

Potency needs to be considered as a function of molecular weight, as increasing MW results in promiscuity and solubility issues

Potency should be increased via the addition of the minimum number of C,N, and O

Question 13

Diversity Space

Answer 13

• Proteome of a binding site which needs to be filled by binding elements
• Combinations and permutations of binding elements seperated by an amount of space. Seperated by bonds i.e. 2-50 A.
• A modestly sized library is required for a protein binding site required with 2 binding sites
• Three binding elements induces an additional dimension and thereby a much larger divesity space is created

Question 14

SAR guided optimization of potency

Answer 14

• Functional groups roles in roles are examined and can be changed to determine their contribution towards binding
• general focus is to define a chemical class with a tractable SAR relationship, develope new IP, develop suitable ADME and PK parameters from early proof of concept experiments in cellular and animal models

Question 15

Ways in which to modify hits

Answer 15

• Modify the periphery, functionalize so groups can easily be attatched
• Modify the core

Question 16

Chemical Modifications which can be used to improve potency

Answer 16

• Increasing SP3 content- improves selectivity (but adds chirality) and solubility
• Cyclisization, conformational lock: Pharmacophores are held into place

Steric Bias i.e. adding a methyl group to select for the more potent conformer

Question 17

Systematic exposure

Answer 17

Desires: 10-20 h which aproximates 3-7 hours in rat ans 2-4 in mouse

Question 18

Improving permeability

Answer 18

• Remove ionic groups/modulate pKa
• Reduce PSA
• Increase LogP (only if very low)
• Retain solubility

Question 19

Short Half-Life

Answer 19

• Verify Clearance: metabolism or transport: renal/liver/other
• Determine metabolite ID via LCMS
• Biosteric replacement
• Reduce LogP

Question 20

Testing Solubility

Answer 20

Kinetic Solubility: Concentration at which a drug (added as DSMO) solution begins to ppt from aq buffer solution (pH = 6.5)

Question 21

Testing Permeability

Answer 21

Note: Papp-BA/Papp-AB > 2 => PGP substrate

Question 22

Phase 1 enzymes

Answer 22

1. CYP-p450
2. FMO
3. MOA
4. Esterases and amidases
5. Alcohol Dehydrogenase

Question 23

Phase 2 enzymes:

Answer 23

1. UGT
2. ST
3. Acetyl- Transferase
4. Gluthathione-S-Transferase

Question 24

Aromatic Oxidation

Answer 24

Remedy: Replace H with F (bioistere) or CH with N

Question 25

Methy and Alkyl group oxidation

Answer 25

Remedy: Flouro-bioestere or deuterium

Question 26

Ester/Amide hydolrysis

Answer 26

Question 27

Dealkylation

Answer 27

Question 28

Vd

Answer 28

Increasing Vd will increase (T1/2) Anionic drugs: Show high plasma protein binding, are confined to body water Neutral drugs: Show even distribution: moderate Vd, increases with lipophilicity Basic Cationic Drugs: Show high tissue binding: High Vd \> 8 L/kg To improve Vd, acid/anions can be replaced with higher pKa biosteres