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Risdiplam

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Chemistry

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Also known as: 1825352-65-5, Rg7916, Evrysdi, Ro7034067, Risdiplam [inn], Risdiplam [usan]

Molecular Formula

C₂₂H₂₃N₇O

Molecular Weight

401.5 g/mol

InChI Key

ASKZRYGFUPSJPN-UHFFFAOYSA-N

FDA UNII

76RS4S2ET1

Risdiplam is an orally bioavailable mRNA splicing modifier used for the treatment of spinal muscular atrophy (SMA). It increases systemic SMN protein concentrations by improving the efficiency of SMN2 gene transcription. This mechanism of action is similar to its predecessor [nusinersen], the biggest difference being their route of administration: nusinersen requires intrathecal administration, as does the one-time gene therapy [onasemnogene abeparvovec], whereas risdiplam offers the ease of oral bioavailability. Risdiplam was approved by the FDA in August 2020 for use in patients 2 months of age or older in the treatment of spinal muscular atrophy (SMA). Set to be substantially cheaper than other available SMA therapies, risdiplam appears to provide a novel and relatively accessible treatment option for patients with SMA regardless of severity or type.

1 2D Structure

Risdiplam

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one

2.1.2 InChI

InChI=1S/C22H23N7O/c1-14-9-18(26-29-11-15(2)24-21(14)29)17-10-20(30)28-12-16(3-4-19(28)25-17)27-8-7-23-22(13-27)5-6-22/h3-4,9-12,23H,5-8,13H2,1-2H3

2.1.3 InChI Key

ASKZRYGFUPSJPN-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC1=CC(=NN2C1=NC(=C2)C)C3=CC(=O)N4C=C(C=CC4=N3)N5CCNC6(C5)CC6

2.2 Other Identifiers

2.2.1 UNII

76RS4S2ET1

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 7-(4,7-diazaspiro(2.5)oct-7-yl)-2-(2,8-dimethylimidazo(1,2-b)pyridazin-6-yl)-4h-pyrido(1,2-a)pyrimidin-4-one

2.3.2 Depositor-Supplied Synonyms

1. 1825352-65-5

2. Rg7916

3. Evrysdi

4. Ro7034067

5. Risdiplam [inn]

6. Risdiplam [usan]

7. Rg-7916

8. 76rs4s2et1

9. Ro-7034067

10. 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one

11. 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(4,7-diazaspiro[2.5]octan-7-yl)-4h-pyrido[1,2-a]pyrimidin-4-one

12. 4h-pyrido(1,2-a)pyrimidin-4-one, 7-(4,7-diazaspiro(2.5)oct-7-yl)-2-(2,8-dimethylimidazo(1,2-b)pyridazin-6-yl)-

13. Evrysdi (tn)

14. Risdiplam; Rg7916

15. Risdiplam [jan]

16. Risdiplam [mi]

17. Risdiplam [usan:inn]

18. Risdiplam [who-dd]

19. Unii-76rs4s2et1

20. Risdiplam (jan/usan/inn)

21. Risdiplam [orange Book]

22. Chembl4297528

23. Schembl17260852

24. Gtpl11170

25. Dtxsid701109185

26. Amy23728

27. Ex-a2074

28. Mfcd31657372

29. Who 10614

30. Compound 1 [pmid: 30044619]

31. Db15305

32. Ac-36304

33. Br166842

34. Rg7916;ro7034067

35. Hy-109101

36. Cs-0039501

37. D11406

38. F53623

39. Q48969152

40. (7-(4,7-diazaspiro(2.5)octan-7-yl)-2-(2,8-dimethylimidazo(1,2-b)pyridazin-6-yl)pyrido(1,2-a)pyrimidin-4-one

41. 7-(4,7-diazaspiro(2.5)oct-7-yl)-2-(2,8-dimethylimidazo(1,2-b)pyridazin-6-yl)-4h-pyrido(1,2-a)pyrimidin-4-one

2.4 Create Date

2016-02-23

3 Chemical and Physical Properties

Molecular Formula	C₂₂H₂₃N₇O
Molecular Weight	401.5 g/mol
XLogP3	0.5
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	2
Exact Mass	401.19640838 g/mol
Monoisotopic Mass	401.19640838 g/mol
Topological Polar Surface Area	78.1 Å²
Heavy Atom Count	30
Formal Charge	0
Complexity	886
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Risdiplam is indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older.

Evrysdi is indicated for the treatment of 5q spinal muscular atrophy (SMA) in patients 2 months of age and older, with a clinical diagnosis of SMA Type 1, Type 2 or Type 3 or with one to four SMN2 copies.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Risdiplam helps to alleviate symptoms of spinal muscular atrophy by stimulating the production of a critical protein in which these patients are deficient. Early trials with risdiplam demonstrated up to a 2-fold increase in SMN protein concentration in SMA patients after 12 weeks of therapy.

5.2 MeSH Pharmacological Classification

Neuromuscular Agents

Drugs used for their actions on skeletal muscle. Included are agents that act directly on skeletal muscle, those that alter neuromuscular transmission (NEUROMUSCULAR BLOCKING AGENTS), and drugs that act centrally as skeletal muscle relaxants (MUSCLE RELAXANTS, CENTRAL). Drugs used in the treatment of movement disorders are ANTI-DYSKINESIA AGENTS. (See all compounds classified as Neuromuscular Agents.)

5.3 ATC Code

M09AX10

M - Musculo-skeletal system

M09 - Other drugs for disorders of the musculo-skeletal system

M09A - Other drugs for disorders of the musculo-skeletal system

M09AX - Other drugs for disorders of the musculo-skeletal system

M09AX10 - Risdiplam

5.4 Absorption, Distribution and Excretion

Absorption

The T_max following oral administration is approximately 1-4 hours. Following once-daily administration with a morning meal (or after breastfeeding), risdiplam reaches steady-state in approximately 7-14 days. The pharmacokinetics of risdiplam were found to be approximately linear between all studied dosages in patients with SMA.

Route of Elimination

Following the oral administration of 18mg risdiplam, approximately 53% of the dose was excreted in the feces and 28% was excreted in the urine. Unchanged parent drug comprised 14% of the dose excreted in feces and 8% of the dose excreted in urine.

Volume of Distribution

Following oral administration, risdiplam distributes well into the central nervous system and peripheral tissues. The apparent volume of distribution at steady-state is 6.3 L/kg.

Clearance

For a 14.9kg patient, the apparent clearance of risdiplam is 6.3 L/kg.

5.5 Metabolism/Metabolites

The metabolism of risdiplam is mediated primarily by flavin monooxygenases 1 and 3 (FMO1 and FMO3), with some involvement of CYP1A1, CYP2J2, CYP3A4, and CYP3A7. Parent drug comprises approximately 83% of circulating drug material. A pharmacologically-inactive metabolite, M1, has been identified as the major circulating metabolite - this M1 metabolite has been observed _in vitro_ to inhibit MATE1 and MATE2-K transporters, similar to the parent drug.

5.6 Biological Half-Life

The terminal elimination half-life of risdiplam is approximately 50 hours in healthy adults.

5.7 Mechanism of Action

Spinal muscular atrophy (SMA) is a severe and progressive congenital neuromuscular disease resulting from mutations in the survival of motor neuron 1 (_SMN1_) gene responsible for making SMN proteins. Clinical features of SMA include degeneration of motor neurons in the spinal cord which ultimately leads to muscular atrophy and, in some cases, loss of physical strength. SMN proteins are expressed ubiquitously throughout the body and are thought to hold diverse intracellular roles in DNA repair, cell signaling, endocytosis, and autophagy. A secondary _SMN_ gene (_SMN2_) can also produce SMN proteins, but a small nucleotide substitution in its sequence results in the exclusion of exon 7 during splicing in approximately 85% of the transcripts - this means that only ~15% of the SMN proteins produced by _SMN2_ are functional, which is insufficient to compensate for the deficits caused by _SMN1_ mutations. Emerging evidence suggests that many cells and tissues are selectively vulnerable to reduced SMN concentrations, making this protein a desirable target in the treatment of SMA. Risdiplam is an mRNA splicing modifier for _SMN2_ that increases the inclusion of exon 7 during splicing, which ultimately increases the amount of functional SMN protein produced by _SMN2_. It does so by binding to two sites in _SMN2_ pre-mRNA: the 5' splice site (5'ss) of intron 7 and the exonic splicing enhancer 2 (ESE2) of exon 7.

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