Lead Flashcards
Key criteria for a lead series
Key criteria for a lead series
* Binding/functional potency in primary assay (IC50 < 100nM)
* Potency in secondary assay (cell proliferation GI50 <500nM)
* Meets Lipinski rules (of 5) (MW<500, cLogP<5)
* In vitro ADME liabilities (t½ >60min)
* Synthesis in less than 10 steps
* Multiple points of modification
* Patentable
Chemical Modification
Goal: Determine Structure- activity relationships:
What functional groups are important to biological activity?
Procedure: Alter or remove groups using chemical synthesis
and test the activity of the altered molecule (analog). Infer role of those groups in binding.
Bioisosteric Replacement
Substitution of atoms or groups of atoms in the parent molecule to produce compounds with broadly similar biological properties to the parent with structural diversity
* Monovalent -F, -OH, -NH2, -SH, -t-C4H9
* Bivalent -O-, -S-, -CH2-, -NH-
* Trivalent -N=, -P=, -CH=
* Hydroxyl -OH, -CH2OH, -NHCOR, -NHCN
* Carbonyl -C=O, C=C(CN)2, =CHCN
* Carboxyl -COOH, -SO 3H, -CONHOH
* Halogen -Cl, -CF3, -CN, -N(CN) 2, -C(CN) 3
* Spacer -(CH2) 3-, -C6H4-
Bioesteric Replacement Example
Resveratrol + Phenyl ring substitution = Compound 13g
-> Bioisosteric replacement increases apoptosis and leukemia cell differentiation
Absorption
H2O Solubility: Essential of intravenous administration and dissolution in GI tract
Acid/Base Properties: Affects solubility in GI Tract.
Physiological range: pKa 1.5-8
Lipophilicity: Influences ability of small molecule drugs to pass through lipid bilayer (Both in and out).
Molecular Size: Smaller=better MW<500 daltons
Absorption: Solubility x Permeability
Permeability and Absorption
- Drug absorption
– Oral administration most convenient and cost-effective Absorption takes place mostly from the small intestine
– Rate of dissolution (tablet, capsule, suspension or solution)
– Dependent on the lipophilicity and extent of ionization of the drug
– Complex with ingested food
– Passes through the portal vein and enters the liver, where it may be metabolized
Solubility and stability
- Crucial criterion for drug testing and oral absorption
- Adherence to rule-of-5 should minimize solubility problems
- Solubility is a complex phenomenon not easily modeled
– Experimentally easy to measure and routinely carried out - Stability is measured at different pH and temperatures
pH application
Orally Available Gemcitabine
-Nucleoside analog(cytosine)
-Impairs DNA replication and induces apoptosis
-Intravenous injection
-Prodrug promotes oral-mediated absorption of gemcitabine with less toxicity
GI Tract pH (Fasted)
- Stomach (1.4-2.1)
- Duodenum (2.4-6.8)
- Jejunum (6.0-7.0)
- Ileum (6.5)
Bioavailability
Bioavailability/Absorption
* Should be studied as early as possible in the development process because a lack of desired response may be due to a lack of bioavailability
(not reaching the required drug concentration)
* Compounds can be suitably modified to maximize bioavailability
Distribution
Distribution
* A drug is distributed to tissues/organs from the blood stream
* Different drug concentrations are attained in different tissues/organs
* A drug may be preferentially distributed to its target tissue/organ or not at all
Clearance
Clearance
* Drugs may be eliminated either unchanged (as the parent drug) or as metabolites depending on the lipophilicity
* Most drugs are eliminated through the kidneys which can excrete only relatively polar substances
* Thus lipophilic drugs must be metabolized into more polar metabolites for elimination
Metabolism
- Drugs are metabolized to different extent mostly in the liver
- Metabolism mostly lead to inactivation of a drug but many drugs have active metabolites
- Therefore important to study the metabolism of a drug under development in order to know the impact it may have
- First studied in liver microsomes
- CYP enzymes inhibition – Drug-drug interactions
Met phase I
Metabolism
* Phase I: Functionalization (CYP450 enzymes): Alteration of functional groups through monooxygenase rxn = loss of activity
Paclitaxel
-Tubulin targeted therapy
-Mitotic inhibitor
-FDA approved for ovarian, breast, lung, bladder, head and neck, esophagus and other cancers
-metabolites are inactive
Met Phase II
*Phase II: Conjugation
* Addition of highly polar conjugates = rapid excretion
Irinotecan
-Active metabolite (SN-38)
-Topoisomerase 1 inhibitor
-Approved for colon, lung and other cancers
-UGTs inactivate SN-38
-addition of glucuronic acid
-UGT1A1*28 polymorphism
-Causes greater toxicity
Animal-based models
- Required for efficacy and toxicity drug evaluation
- Validate in vivo biomarkers for drug efficacy
- In vivo evaluation of PK/PD in normal and disease animal models
- In vivo efficacy evaluation
- Dynamic evaluation of drug efficacy
– Histological analysis
– Tissue sample analysis (RNA, DNA, Protein)
– In vivo imaging of disease progression