KW-6356

KW-6356 (INN sipagladenant) is a synthetic small molecule that acts at the adenosine A2A receptor. It blocks adenosine binding and also inhibits the receptor's constitutive (adenosine-independent) activity, so its developer, Kyowa Kirin, calls it an A2A antagonist/inverse agonist (Ohno et al., 2023).

PubChem CID 23144148, filed under the name Sipagladenant, lists the same formula, weight and CAS number and supplied the aliases and structure.

Published work on KW-6356 falls into six areas. Each summary below states the model used. Outside the human pharmacokinetic and trial papers, the evidence is in vitro and marmoset data. All six primary KW-6356 papers in PubMed have Kyowa Kirin authors.

Receptor binding and inverse agonism

In the developer's in vitro profile, KW-6356 bound the human A2A receptor potently and selectively (pKi 9.93, an inhibition constant near 0.12 nanomolar) and dissociated very slowly (rate constant 0.016 per minute). Functional assays showed insurmountable antagonism and inverse agonism, against surmountable antagonism for istradefylline. Co-crystal structures tied inverse agonism to His250 and Trp246 contacts and suggested that contacts deep in the pocket and at a lid steadying the extracellular loops underlie the insurmountable block (Ohno et al., 2023).

A review co-written by Kyowa Kirin scientists argues that because an inverse agonist, unlike a neutral antagonist, also removes constitutive receptor activity, it is more likely to show motor effects on its own (Mori et al., 2022). Models: binding and functional assays, X-ray crystallography.

How it differs from istradefylline

Istradefylline (KW-6002), an 8-styrylxanthine from the same company, reversed drug-induced catalepsy and lessened MPTP- or reserpine-induced hypolocomotion in mice (Shiozaki et al., 1999), and it reversed motor disability in MPTP-treated marmosets with little or no dyskinesia in L-DOPA-primed animals (Kanda et al., 1998).

KW-6356 adds inverse agonism and, in a head-to-head marmoset study, produced a significantly larger anti-parkinsonian effect than istradefylline (Ohno et al., 2023). No rodent Parkinson's model study of KW-6356 itself is indexed in PubMed; the rodent work in this line is istradefylline's. Models: mice, marmosets and a human trial.

Parkinsonian marmosets

In common marmosets made parkinsonian with MPTP, KW-6356 given by mouth reversed motor disability, with larger effects at higher amounts up to 1 mg/kg, and repeated exposure induced little dyskinesia in L-DOPA-primed animals (Ohno et al., 2023). In a companion study, KW-6356 at 1 mg/kg strengthened the motor response to L-DOPA (2.5 to 10 mg/kg) and, in primed animals, did not add to dyskinesia.

Over 21 days with L-DOPA at 2.5 mg/kg, dyskinesia rose above that of this low L-DOPA alone but stayed below the level produced by L-DOPA at 10 mg/kg (Ohno et al., 2023). Every author of both studies worked for Kyowa Kirin, which funded the companion study. Model: MPTP-treated common marmosets.

Pharmacokinetics in people

Two phase 1 studies, with randomized placebo-controlled and open-label parts, gave healthy Japanese and White volunteers single rising amounts and once-daily amounts for 14 days. KW-6356 was reported as well tolerated, with linear pharmacokinetics over the single-amount range, a mean terminal elimination half-life of 18.4 to 43.1 hours after single amounts and no clear difference between Japanese and White participants (Tayama et al., 2023).

A population model pooling healthy-volunteer and Parkinson's disease data fitted one-compartment models to KW-6356 and its active metabolite M6; food status, serum albumin and body weight were covariates, none with a clinically meaningful effect on exposure (Tayama et al., 2024). Models: healthy adults and people with Parkinson's disease.

Parkinson's disease trials

The published phase 2 monotherapy trial (NCT02939391) randomized 168 people in Japan with early Parkinson's disease, not yet on anti-Parkinson medication, to placebo or one of two once-daily amounts for 12 weeks. Least squares mean MDS-UPDRS Part III scores, the primary endpoint, fell 5.37 points on the lower amount, 4.76 on the higher and 3.14 on placebo. Both KW-6356 groups changed more than placebo at every time point and secondary endpoints agreed; the abstract gives no p values.

Constipation and nasopharyngitis were the most common adverse events on KW-6356 (Maeda et al., 2023). A larger phase 2 trial, NCT03703570, added KW-6356 or placebo to levodopa-containing regimens, with MDS-UPDRS Part III change as the primary outcome (Ntetsika et al., 2021). Kyowa Kirin announced in October 2020 that it met that endpoint in 502 participants over 26 weeks, and the company's later papers cite adjunct efficacy (Ohno et al., 2023), but no full peer-reviewed report is indexed in PubMed. Models: randomized human trials.