Surlorian

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Surlorian

CAS 1467605-57-7

MFC18H19NO3S, 329.41

4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl]benzoic acid
ryanodine receptor (RyR) stabilizer, ARM 210, RYCAL DMD, s48168, S 48168, 1033GN605L

Surlorian (ARM210) is a novel drug candidate, specifically a Ryanodine Receptor (RyR) stabilizer developed by RyCarma Therapeutics, designed to treat heart failure by repairing leaky RyRs in heart and skeletal muscles, aiming to improve both cardiac function and muscle weakness by restoring normal calcium regulation. It’s an allosteric modulator, a “Rycal,” that fixes these crucial calcium channels without blocking them, addressing a core issue in heart failure and related muscle diseases.

Key Aspects:

Mechanism: It stabilizes damaged RyR channels, which become leaky due to stress (like in heart failure), preventing unregulated calcium leakage from the sarcoplasmic reticulum (SR).
Target: Acts systemically on RyRs in both cardiac (heart) and skeletal (muscle) cells.
Benefits: Aims to improve heart contraction/relaxation and alleviate skeletal muscle weakness, a common heart failure symptom.
Therapeutic Area: Heart failure, potentially addressing underlying calcium dysregulation.
Status: In clinical development, with Phase II trials underway as of mid-2025, according to AdisInsight.
Chemical Info: Molecular Formula: C18H19NO3S; CAS No: 1467605-57-7.

In essence, Surlorian offers a new approach to heart failure by fixing the fundamental calcium handling problem in muscles, rather than just managing symptoms.

OriginatorARMGO Pharma
DeveloperNational Institute of Neurological Disorders and Stroke; RyCarma Therapeutics; Servier
ClassAntiarrhythmics; Heart failure therapies; Small molecules
Mechanism of ActionRyanodine receptor calcium release channel modulators
Orphan Drug StatusYes – Polymorphic catecholergic ventricular tachycardia; Congenital structural myopathies; Duchenne muscular dystrophy
Phase IIPolymorphic catecholergic ventricular tachycardia
Phase ICardiac-arrhythmias; Congenital structural myopathies; Heart failure
No development reportedDuchenne muscular dystrophy; Limb girdle muscular dystrophies; Sarcopenia; X-linked bulbo-spinal atrophy
04 Sep 2025Chemical structure information added.
02 Apr 2025Surlorian is still in phase I trial for Congenital structural myopathies in USA (PO) (NCT04141670)
02 Apr 2025Phase-I clinical trials in Heart failure (unspecified route), prior to April 2025 (RyCarma Therapeutics pipeline, April 2025)

Treatment of an Inherited Ventricular ArrhythmiaCTID: NCT05122975Phase: Phase 2Status: TerminatedDate: 2024-09-19
S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)CTID: NCT04141670Phase: Phase 1Status: CompletedDate: 2024-08-22

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https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=7D2A432BCEB72512228EE7E0314A4982.wapp2nB?docId=US456995370&_cid=P21-MIV3Q0-83794-1

EXAMPLE 1: PREPARATION OF 4-[(7-METHOXY-2,3-DIHYDRO-1,4-BENZOTHIAZEPIN-4(5H)YL)METHYL]BENZOIC ACID

4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was prepared as described below.

Stage 1: 7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (“Amine”)

2-(4-Methoxyphenylthio)ethanamine (1)

4-Methoxythiophenol (50 g, 0.357 mol), 2-chloroethylamine monohydrochloride (39.8 g, 0.343 mol.), K₂CO₃ (78.8 g, 0.57 mol) and diisopropyl ethylamine (32 mL, 0.178 mol) were mixed in tetrahydrofuran (THF). The mixture was degassed for 5 min. under reduced pressure and heated at reflux under argon overnight. The solvent was removed and water was added to the flask. The mixture was extracted with dichloromethane. The organic layers were collected, dichloromethane was removed and conc. HCl was added, followed by of water. The solution was extracted with 1:1 ethyl acetate (EtOAc)/hexane. The aqueous layer was adjusted to pH 10 with 2 M NaOH, and was extracted with dichloromethane. The combined organic solution was dried over anhydrous sodium sulfate. Removal of solvent provided the target compound.

Benzyl 2-(4-methoxyphenylthio)ethylcarbamate (2)

To a flask containing compound 1 (8.0 g, 43.7 mmol), sodium bicarbonate (12.1 g, 144 mmol), water, and dichloromethane was added benzyl chloroformate (8.2 g, 48.1 mmol, diluted in 100 mL of dichloromethane) dropwise at 0° C. After the addition, the mixture was stirred at r.t. for 5 hr. The organic layer was collected and the aqueous solution was extracted with 100 mL of dichloromethane. The combined organic solution was dried over sodium sulfate. The solvent was removed and the resulting solid was triturated with THF/hexane (1:10). The solid was collected and dried leaving the target product.

Benzyl 7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepine-4(5H)-carboxylate (3)

A mixture of compound 2 (7.3 g, 23 mmol), paraformaldehyde (6.9 g 0.23 mol), and p-toluenesulfonic acid (1.45 g, 7.6 mmol) in toluene was stirred at 70° C. overnight. After cooling to r.t., the solid was filtered off. The solution was extracted with saturated sodium carbonate, and the organic layer was dried over anhydrous sodium sulfate to yield the target product as a liquid after removal of the solvent.

7-Methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine hydrobromide (Amine)

Compound 3 (10 g, 30 mmol) was mixed with concentrated HCl, water and dioxane. The mixture was stirred at 100° C. overnight. After cooling to room temperature, most of the solvent and HCl were removed under reduced pressure. Water was added to the solution and the solid was filtered off. The aqueous solution was extracted with EtOAc/hexane (1:1) and basified by adding 15 g of NaOH. The mixture was extracted with dichloromethane. The combined solution was dried over anhydrous sodium sulfate. Removal of solvent provided a liquid that solidified after standing at room temperature (r.t.), to yield the target compound.

Stage 2: −[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid

In Scheme 2, L is a leaving group, which is, by way of example, a halogen or a sulfonate (OSO ₂R′ wherein R′is alkyl or aryl, e.g., OMs (mesylate) or OTs (tosylate)). Amine (4) (1 mmol) was dissolved dichloromethane. To the solution was added alkylation reagent (5) (1 mmol), followed by N,N-diisopropylethylamine (2 mmol). The mixture was stirred at room temperature overnight. The solution was loaded onto a silica gel column directly and eluted with hexane/EtOAc (2:1, v/v) to afforded the desired product.

SYN

WO-2013156505

PAT