Sipagladenant Explained

Image Class:	skin-invert-image
Width:	250px
Routes Of Administration:	Oral
Class:	Adenosine A_2A receptor antagonist; Antiparkinsonian agent
Atc Prefix:	None
Onset:	0.75–3 hours
Elimination Half-Life:	18.4–43.1 hours^[1]
Cas Number:	858979-50-7
Pubchem:	23144148
Drugbank:	DB17080
Unii:	FF2012ZV92
Chembl:	5314441
Pdb Ligand:	JQR
Synonyms:	KW-6356; KW6356
Iupac Name:	N-(4-(furan-2-yl)-5-(tetrahydro-2H-pyran-4-carbonyl)thiazol-2-yl)-6-methylnicotinamide
C:	20
H:	19
N:	3
O:	4
S:	1
Smiles:	CC1=NC=C(C=C1)C(=O)NC2=NC(=C(S2)C(=O)C3CCOCC3)C4=CC=CO4
Stdinchi:	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)
Stdinchikey:	KMFLQPJJHQNKKF-UHFFFAOYSA-N

Sipagladenant (; 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.^[2] ^[3] ^[4] It reached phase 2 clinical trials prior to the discontinuation of its development in 2022.

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.

Pharmacokinetics

The half-life of KW-6356 is 22.9 hours. The half-life of M6 is 4.34 hours.

Development

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

Notes and References

Tayama T, Ishiuchi M, Sugiyama K, Oka Y, Maeda H, Nagata Y, Hruska M, Kagawa Y . 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 . August 2023 . 36683291 . 10.1002/cpdd.1222 .
Web site: Sipagladenant . AdisInsight . 5 November 2023 . 28 January 2026.
Web site: Delving into the Latest Updates on KW-6356 with Synapse . Synapse . 24 January 2026 . 28 January 2026.
Maeda T, Kimura T, Sugiyama K, Yamada K, Hiraiwa R, Nishi M, Hattori N . Randomized controlled trial of KW-6356 monotherapy in patients with early untreated Parkinson's disease . English . Parkinsonism & Related Disorders . 117 . 105907 . December 2023 . 37948832 . 10.1016/j.parkreldis.2023.105907 . free .
Ohno Y, Suzuki M, Asada H, Kanda T, Saki M, Miyagi H, Yasunaga M, Suno C, Iwata S, Saito JI, Uchida S . In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2A Receptor Antagonist/Inverse Agonist . Molecular Pharmacology . 103 . 6 . 311–324 . June 2023 . 36894319 . 10.1124/molpharm.122.000633 .
Web site: Kyowa Kirin Announced Discontinuation of KW-6356 .