SAR of lacosamide
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The document discusses the structural activity relationship of locasamide as a sodium channel blocker. Sodium channels play an important role in nerve signal transmission and have alpha and beta subunits. The alpha subunit forms the pore and is the functional part of the channel. Locasamide is an anticonvulsant drug that blocks sodium channels. It was developed by changing the nitrogen atom in the lead compound to a carbon atom to reduce toxicity while maintaining activity. Structure-activity relationship studies showed that modifications to locasamide's phenyl group, alkyl groups, and 3-oxy site can impact its potency and activity
![References
• Pierre Morieux, et al, ( The Structure-Activity Relationship of the 3-
Oxy Site in the Anticonvulsant (R)-N-Benzyl 2-Acetamido-3-
methoxypropionamide) J Med Chem. 2010.
• Idris et al ,( Synthesis and anticonvulsant studies of isomeric N-
Benzyl 2-Acetamido-3-methoxypropionamide) , Nigerian journal of
pharmaceutical sciences Vol.8 No.1 , March , 2009
• Avoli M, D’Antuono M, Louvel J, et al. Network and pharmacological
mechanisms leading to epileptiform synchronization in the limbic
system. Prog Neurobiol. 2002;68:167–207. [PubMed]](https://image.slidesharecdn.com/lacosemidefinal1-210305211539/85/SAR-of-lacosamide-11-320.jpg)
SAR of lacosamide
- 1. Structural activity realationship of locasamide as as a sodium channel blocker Laith J. Abdulredha Zahraa Najah Muhsin
- 2. Sodium channel blockers • Sodium channel found in CNS, heart and skeletal muscles • Play an important role in the transmission of action potential along the nerve • Two types of Na channels voltage and ligand gated ion channels
- 3. Targeting of sodium channel protein • Sodium channel have two subunits alpha and beta • α subunit is pore forming (functional expression ) • β subunit is modifying kinetics and voltage dependence
- 4. Targeting of sodium channel protein • The α subunits are organized in four domains ( I – IV ) • Each domain contain six α helices (S1 – S6) • S4 segment in each domain contain positively charged amino acid residue • This residue responsible for channel activation (sensor)
- 5. Targeting of sodium channel protein • When a change in transmembrane voltage occur , this segment moves toward the extracellular side of the cell membrane, allowing the channel to become permeable to ions. • The ions are conducted through a pore, which can be broken into two regions.
- 6. Targeting of sodium channel protein • The more external (i.e., more extracellular) portion of the pore is formed by the "P-loops" (the region between S5 and S6) of the four domains. • This region is the most narrow part of the pore and is responsible for its ion selectivity. • The inner portion (i.e., more cytoplasmic) of the pore is formed by the combined S5 and S6 segments of the four domains.
- 7. Lacosamide as a Na channel blocker • Lacosamide (vimpat) is anticonvulsant drug used alone or in combination with other drugs in control certain types of seizures • Chemical name is 2 acetamido-N-benzyl- 3- methoxy propanamide
- 8. Pocket of Na channel
- 9. SAR of locasamide • As illustrated in the diagram above changing the Nitrogen (N) at the modification site (X) of the lead compound to the carbon , creating locasamide to reduce toxicity and improve activity .
- 10. SAR of locasamide • The distal phenyl group are critical for activity. • Alkyl group added to phenyl ring must be linear • Substituted at pyrozole nitrogen with H bond donor will increase potency • Adding a bulky group on 3-oxy site R1 lead to loss of activity
- 11. References • Pierre Morieux, et al, ( The Structure-Activity Relationship of the 3- Oxy Site in the Anticonvulsant (R)-N-Benzyl 2-Acetamido-3- methoxypropionamide) J Med Chem. 2010. • Idris et al ,( Synthesis and anticonvulsant studies of isomeric N- Benzyl 2-Acetamido-3-methoxypropionamide) , Nigerian journal of pharmaceutical sciences Vol.8 No.1 , March , 2009 • Avoli M, D’Antuono M, Louvel J, et al. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system. Prog Neurobiol. 2002;68:167–207. [PubMed]
- 12. Thank you