Sipagladenant

Sipagladenant
Clinical data
Other names	KW-6356; KW6356
Routes of; administration	Oral
Drug class	Adenosine A2A receptor antagonist; Antiparkinsonian agent
ATC code	None;
Pharmacokinetic data
Onset of action	0.75–3 hours (TmaxTooltip time to peak levels)
Elimination half-life	18.4–43.1 hours
Identifiers
	IUPAC name N-(4-(furan-2-yl)-5-(tetrahydro-2H-pyran-4-carbonyl)thiazol-2-yl)-6-methylnicotinamide;
CAS Number	858979-50-7;
PubChem CID	23144148;
DrugBank	DB17080;
UNII	FF2012ZV92;
ChEMBL	ChEMBL5314441;
PDB ligand	JQR (PDBe, RCSB PDB);
Chemical and physical data
Formula	C20H19N3O4S
Molar mass	397.45 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=NC=C(C=C1)C(=O)NC2=NC(=C(S2)C(=O)C3CCOCC3)C4=CC=CO4;
	InChI InChI=InChI=1S/C20H19N3O4S/c1-12-4-5-14(11-21-12)19(25)23-20-22-16(15-3-2-8-27-15)18(28-20)17(24)13-6-9-26-10-7-13/h2-5,8,11,13H,6-7,9-10H2,1H3,(H,22,23,25); Key:KMFLQPJJHQNKKF-UHFFFAOYSA-N;

Sipagladenant (INNTooltip International Nonproprietary Name; developmental code name KW-6356) is a non-xanthine selective antagonist or inverse agonist of the adenosine A_2A receptor that was previously under development by Kyowa Kirin as a monotherapy and adjunctive to levodopa therapy in Parkinsonism.^[1]^[3]^[4]^[5] It reached phase 2 clinical trials prior to the discontinuation of its development in 2022.^[1]^[3]

Pharmacology

Pharmacodynamics

KW-6356 is a selective A_2A adenosine antagonist or inverse agonist displaying insurmountable antagonism of this adenosine subtype. Compared to the first generation A_2A adenosine inverse agonist Istradefylline, KW-6356 possesses a 100-fold greater affinity for the A_2A adenosine receptor and dissociates more slowly from the receptor.^[5]

The metabolism of KW-6356 generates M6, an active metabolite with similar potency as a A_2A antagonist/inverse agonist.^[5]

Pharmacokinetics

The half-life of KW-6356 is 22.9 hours. The half-life of M6 is 4.34 hours.^[5]

Development

Kyowa Kirin halted development of KW-6356 in 2022 based on regulatory and developmental challenges surrounding the drug.^[6]

References

1 2 3 "Sipagladenant". AdisInsight. 5 November 2023. Retrieved 28 January 2026.
1 2 Tayama T, Ishiuchi M, Sugiyama K, Oka Y, Maeda H, Nagata Y, et al. (August 2023). "Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 Following Single and Multiple Oral Administration in Healthy Volunteers". Clin Pharmacol Drug Dev. 12 (8): 801–809. doi:10.1002/cpdd.1222. PMID 36683291.
1 2 "Delving into the Latest Updates on KW-6356 with Synapse". Synapse. 24 January 2026. Retrieved 28 January 2026.
↑ Maeda T, Kimura T, Sugiyama K, Yamada K, Hiraiwa R, Nishi M, et al. (December 2023). "Randomized controlled trial of KW-6356 monotherapy in patients with early untreated Parkinson's disease". Parkinsonism & Related Disorders. 117 105907. doi:10.1016/j.parkreldis.2023.105907. PMID 37948832.
1 2 3 4 Ohno Y, Suzuki M, Asada H, Kanda T, Saki M, Miyagi H, et al. (June 2023). "In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2A Receptor Antagonist/Inverse Agonist". Molecular Pharmacology. 103 (6): 311–324. doi:10.1124/molpharm.122.000633. PMID 36894319.
↑ "Kyowa Kirin Announced Discontinuation of KW-6356" (PDF).

[AdisInsight-1] 1 2 3 "Sipagladenant". AdisInsight. 5 November 2023. Retrieved 28 January 2026.

[TayamaIshiuchiSugiyama2023-2] 1 2 Tayama T, Ishiuchi M, Sugiyama K, Oka Y, Maeda H, Nagata Y, et al. (August 2023). "Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 Following Single and Multiple Oral Administration in Healthy Volunteers". Clin Pharmacol Drug Dev. 12 (8): 801–809. doi:10.1002/cpdd.1222. PMID 36683291.

[Synapse-3] 1 2 "Delving into the Latest Updates on KW-6356 with Synapse". Synapse. 24 January 2026. Retrieved 28 January 2026.

[4] Maeda T, Kimura T, Sugiyama K, Yamada K, Hiraiwa R, Nishi M, et al. (December 2023). "Randomized controlled trial of KW-6356 monotherapy in patients with early untreated Parkinson's disease". Parkinsonism & Related Disorders. 117 105907. doi:10.1016/j.parkreldis.2023.105907. PMID 37948832.

[Ohno_2023-5] 1 2 3 4 Ohno Y, Suzuki M, Asada H, Kanda T, Saki M, Miyagi H, et al. (June 2023). "In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2A Receptor Antagonist/Inverse Agonist". Molecular Pharmacology. 103 (6): 311–324. doi:10.1124/molpharm.122.000633. PMID 36894319.

[6] "Kyowa Kirin Announced Discontinuation of KW-6356" (PDF).

[1]

[2]

[3]

[4]

[5]

[6]

Pharmacology

Pharmacodynamics

Pharmacokinetics

Development

See also

References