Sipagladenant (KW-6356)

What is Sipagladenant (KW-6356)?

Sipagladenant, frequently identified in scientific literature by its developmental code KW-6356 (and occasionally referenced as KW-6353), is a non-xanthine chemical compound. It is classified in pharmacological research as a selective adenosine A2A receptor antagonist.

In molecular biology, this compound serves as a chemical probe. Its primary function in research settings is to block the adenosine A2A receptor, helping scientists understand how these receptors influence brain chemistry and cellular signaling.

Chemical Structure and Composition

KW-6356 (Sipagladenant) — Chemical Specifications

Parameter	Specification
Common Chemical Name	Sipagladenant
Developmental Codes	KW-6356, KW6356, KW-6353
IUPAC Name	N-(4-(furan-2-yl)-5-(tetrahydro-2H-pyran-4-carbonyl)thiazol-2-yl)-6-methylnicotinamide
CAS Registry Number	858979-50-7
PubChem CID	23144148
DrugBank ID	DB17080
Molecular Formula	C₂₀H₁₉N₃O₄S
Molecular Weight	397.45 g·mol⁻¹
Calculated LogP (AlogP)	0.0 to 2.0
Topological Polar Surface Area	89 Å²
Purity (Synthetic/Commercial)	≥ 98%
Primary Physical Form	Off-white to light yellow solid powder
Route of Administration (Research)	Oral

KW-6356 is a heterocyclic molecule. Its structure is engineered to interact specifically with the adenosine A2A receptor, a protein found in the brain. Its chemical design includes:

A central 1,3-thiazole ring: The core framework of the molecule.
Hydrophobic Anchors: Specific attachments, including a furan ring, that allow the molecule to “dock” tightly into the receptor pocket.
Stability Components: Its structural arrangement helps it resist rapid breakdown, a challenge often faced by earlier generation compounds.

Mechanism of Action: Biology of Receptor Blockade

To understand how KW-6356 functions, think of a cellular receptor as a lock and adenosine as the key. Under normal physiological conditions, adenosine acts as the key, binding to the A2A receptor and triggering a signaling cascade in the cell.

Sipagladenant functions as a “jammed key.” It binds to the receptor (the lock) so tightly and specifically that the natural adenosine cannot attach. This process is known as insurmountable antagonism.

Key Pharmacological Actions:

Antagonism: It blocks the activation of the receptor by preventing the binding of natural molecules.
Inverse Agonism: Beyond just blocking the receptor, it also suppresses the “constitutive activity” or the baseline chatter of the receptor that occurs even without adenosine present.

Research Development and Status

Between its initial development and 2022, KW-6356 was studied in various experimental models to investigate its potential role in managing neurobiological signals. These studies examined its effects on motor control and cognitive function in animal models.

In 2022, the program associated with the clinical investigation of this compound for specific neurological conditions was discontinued following a strategic review of global regulatory and development timelines.

Current Status:

Sipagladenant remains a valuable chemical probe in academic and laboratory research. It is used to investigate pathways in neurodegeneration, the tumor microenvironment (immunology), and basic receptor kinetic studies.

Study ID (NCT Number)	Trial Phase and Design	Patient Population and Sample Size	Primary Endpoint and Key Clinical Outcomes
NCT02939391	Phase 2a; Randomized, double-blind, placebo-controlled, monotherapy	Early-stage research subjects with untreated Parkinson’s disease	MDS-UPDRS Part III Score at Week 12: Both active groups met the primary endpoint. The research was well-tolerated, with constipation and nasopharyngitis reported as the most common adverse events.
NCT03703570	Phase 2b; Randomized, double-blind, placebo-controlled, adjunctive to levodopa	Research subjects with Parkinson’s disease experiencing motor fluctuations on stable levodopa	MDS-UPDRS Part III Score at Week 26: Both active groups showed significant improvement.
NCT04342273	Phase 1; Thorough QT/QTc evaluation	Healthy research subjects	Electrocardiographic Safety: Evaluated the effects of sipagladenant on the QT/QTc interval. No clinically relevant QTc prolongation or cardiac safety signals were observed.
NCT04190654	Phase 1; Hepatic impairment pharmacokinetic study	Research subjects with mild or moderate hepatic impairment vs. normal hepatic function	Pharmacokinetic Profile: Evaluated the effect of hepatic impairment on the clearance of the parent drug and the formation of the M6 metabolite.
NCT04070495	Phase 1; Drug-drug interaction study	Healthy research subjects	CYP3A4/5 Interaction Assessment: Quantified changes in sipagladenant exposure when co-administered with strong CYP3A4/5 inhibitors or inducers, confirming the key role of the CYP3A4/5 pathway in its clearance.

Research Articles

Here are articles related to KW-6356 / Sipagladenant

Discovery of Novel Dual Adenosine A2A and A1 Receptor Antagonists with 1H-Pyrazolo[3,4-d]pyrimidin-6-amine Core Scaffold as Anti-Parkinson’s Disease Agents – PMC
In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A 2A Receptor Antagonist/Inverse Agonist | ResearchGate
Role of Cardiac A2A Receptors Under Normal and Pathophysiological Conditions – PMC
A2A adenosine receptor agonists, antagonists, inverse agonists and partial agonists – PMC
Anti-parkinsonian activity of the adenosine A2A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets – ResearchGate
Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW‐6356 Following Single and Multiple Oral Administration in Healthy Volunteers – ResearchGate
Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson’s Disease – PubMed
NCT02939391 | A Study of KW-6356 in Subjects With Early Parkinson’s Disease
NCT03703570 | A Study of KW-6356 in Patients With Parkinson’s Disease on Treatment With Levodopa-containing Preparations | ClinicalTrials.gov
Therapeutic potential of adenosine receptor modulators in cancer treatment – RSC Publishing
Development of Adenosine A 2A Receptor Antagonists for the Treatment of Parkinson’s Disease: A Recent Update and Challenge – ACS Publications
Phase 2b tozadenant study (not completed). | Download Scientific Diagram – ResearchGate
The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease – PMC
An Open-Label, Positron Emission Tomography Study to Assess Adenosine A2A Brain Receptor Occupancy of Vipadenant (BIIB014) at Steady-State Levels in Healthy Male Volunteers | Request PDF – ResearchGate
(PDF) A2A adenosine receptor agonists, antagonists, inverse agonists and partial agonists
Crystal structure of adenosine A2A receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction – PMC
Adenosine receptors on the immuno-oncology expressway: TIME, perspectives, and translation – PMC
Adenosine Receptors in Neuroinflammation and Neurodegeneration – PMC – NIH
Adenosine receptors on the immuno-oncology expressway: TIME, perspectives, and translation – Frontiers

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KW-6353 (Sipagladenant)

KW-6353 (Sipagladenant)