Abstract
The optimization and discovery of small molecule drugs has evolved in the past decades. Since the mid-1990s, in vitro ADME assays have allowed for systematic optimization of molecules based on key ADME attributes. This has had a huge impact on the molecular design cycles: design, synthesis, assessment and re-design.
In this chapter, we discuss the strategies for optimization of small molecules during drug discovery and address various ADME liabilities that exist during small molecule optimization. We have included many examples to allow for dissecting the problems and complexities of a real world drug discovery.
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Abbreviations
- ABC:
-
ATP-binding cassette transporters
- ASBT:
-
Ileal apical sodium/ bile acid co-transporter.
- AUC :
-
Area under the blood/plasma concentration-time profile
- AUC Extravascular :
-
AUC following an extravascular dose (i.e. oral, subcutaneous, intraperitoneal)
- AUC IV :
-
AUC following an intravenous dose
- BCRP:
-
Breast cancer resistance protein
- BSEP:
-
Bile-salt export pump
- CL :
-
Clearance
- C max :
-
Highest or peak blood/plasma concentration
- DME:
-
Drug metabolizing enzymes
- E :
-
Extraction ratio
- F :
-
Bioavailability
- f u :
-
Unbound fraction in blood/plasma
- f uT :
-
Unbound fraction in tissue
- HBA:
-
Hydrogen bond acceptors
- HBD:
-
Hydrogen bond donors
- LC:
-
Liquid chromatography
- LM:
-
Large molecules
- MATE:
-
Multidrug and toxin extrusion protein
- MCT:
-
Monocarboxylic acid transporter
- MRP:
-
Multidrug resistance-associated protein
- MS:
-
Mass spectrometry
- NM:
-
New modalities
- NTCP:
-
Sodium/taurcholate co-transporting peptide
- OAT:
-
Organic anion transporter
- OATP:
-
Organic anion transporting polypeptides
- OCT:
-
Organic cation transporter
- OCTN :
-
Organic cation/ carnitine transporter
- OSTα-OSTβ:
-
Heteromeric organic solute transporter
- PEPT:
-
Peptide transporter
- P-gp:
-
P-glycoprotein
- PPB:
-
Plasma protein binding
- SLC:
-
Solute carrier transporters
- SM:
-
Small molecules
- Q :
-
Hepatic blood flow
- V d :
-
Volume of distribution
- t 1/2 :
-
Half-life
- t max :
-
Time at which Cmax occurs
- URAT1:
-
Urate transporter
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Khojasteh, S.C., Wong, H., Zhang, D., Hop, C.E. (2022). DMPK Lead Optimization. In: Discovery DMPK Quick Guide. Springer, Cham. https://doi.org/10.1007/978-3-031-10691-0_3
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