Lirucitinib

 

Lirucitinib

CAS 2458115-78-9

MF C16H25N5OS MW335.5 g/mol

N-[4-[(ethylsulfonimidoyl)methyl]cyclohexyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

(R)-ethyl(imino)({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methyl)-λ6
-sulfanone
Janus tyrosine kinase inhibitor, anti-inflammatory, GGW101, GGW 101

Lirucitinib is a Janus kinase (JAK) inhibitor primarily known as a novel, Class I veterinary drug. It specifically targets the JAK1 enzyme to block itch-inducing (pruritic) and inflammation-causing cytokines in the body.

Core Information

• Primary Use: The drug is developed for veterinary medicine to treat acute and chronic pruritic (severe itch) skin diseases in dogs, which are commonly caused by allergies, parasites, or infections.
• Approval Status: It received a Class I New Veterinary Drug Certificate from the Ministry of Agriculture and Rural Affairs (MARA) in China.
• Human Medicine: As of 2026, there are no clinical indications or indications that Lirucitinib is being tested for use in humans.
• Chemical Profile: It is an orally active small molecule with the chemical formula C₁₆H₂₅N₅OS and acts specifically as the (R)-enantiomer of the compound.

SYN

[US20220106319A1]

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=4CA57DF508E7B72B516CEB2A97283182.wapp2nC?docId=US356967355&_cid=P22-MQQ0KW-29134-1

  11 (1.0 g, 2.04 mmol) (prepared in step 9), tetrahydrofuran/methanol (10 mL), and cesium carbonate (1.33 g, 4.08 mmol) were added into a 25 mL single-necked flask, refluxed for 12 h, concentrated, and poured into dichloromethane and saturated salt solution, the organic phase was dried with anhydrous sodium sulfate, concentrated, and subjected to a conventional preparation method and a chiral preparation method to obtain product A as a white solid (20 mg, yield: 2.9%), LC-MS: 336 [M+H]+, H ¹-NMR: ¹H NMR (400 MHz, DMSO) δ 11.61 (s, 1H), 8.09 (s, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 4.67 (s, 1H), 3.90-3.83 (m, 1H), 3.17 (s, 3H), 3.06-2.93 (m, 4H), 2.12-2.01 (m, 3H), 1.73-1.70 (m, 4H), 1.31-1.22 (m, 5H) and product B as a white solid (25 mg, yield: 3.7%), LC-MS: 336 [M+H]+, H ¹—NMR: ¹H NMR (400 MHz, DMSO) δ 11.59 (s, 1H), 8.09 (s, 1H), 7.12 (dd, J=3.3, 2.6 Hz, 1H), 6.54 (s, 1H), 4.67 (s, 1H), 3.58 (s, 1H), 3.17 (s, 3H), 3.06-2.89 (m, 4H), 2.16-1.93 (m, 3H), 1.74-1.69 (m, 4H), 1.25-1.23 (m, 5H).

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PAT

• Jak inhibitor and preparation method thereforPublication Number: EP-3915989-B1Priority Date: 2019-01-30Grant Date: 2023-06-28
• Jak inhibitor and preparation method thereforPublication Number: US-2022106319-A1Priority Date: 2019-01-30
• Jak inhibitor and preparation method thereforPublication Number: WO-2020155931-A1Priority Date: 2019-01-30
• Jak inhibitor and preparation method thereforPublication Number: EP-3915989-A1Priority Date: 2019-01-30

/////////lirucitinib, anax labs, Janus tyrosine kinase inhibitor, anti-inflammatory, GGW101, GGW 101

#lirucitinib, #anax labs, #Janus tyrosine kinase inhibitor, #anti-inflammatory, #GGW101, #GGW 101

Lixosicone

 

Lixosicone

CAS 1610878-71-1

MF C29H40O3 MW 436.6 g/mol

1-[(3S,8S,9S,10R,13S,14S,17S)-3-[(4-methoxyphenyl)methoxy]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone

• 3beta-[(4-methoxyphenyl)methoxy]pregn-5-en-20-one
• (3beta)-3-[(4-Methoxyphenyl)methoxy]pregn-5-en-20-one
• Pregn-5-en-20-one, 3-[(4-methoxyphenyl)methoxy]-, (3beta)-
• 1-[(3S,8S,9S,10R,13S,14S,17S)-3-[(4-methoxyphenyl)methoxy]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone
• 3?-(4-Methoxybenzyloxy)pregn-5-en-20-one; 1-((3S,8S,9S,10R,13S,14S,17S)-3-((4-Methoxybenzyl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

3β-[(4-methoxyphenyl)methoxy]pregn-5-en-20-one
cannabinoid CB1 receptor signalling inhibitor, AEF0117, AEF 0117, 9LG9CT78SV

AEF0117 is a small molecule drug. AEF0117 is under investigation in clinical trial NCT05554926 (Study of [4-14C] AEF0117 Following a Single Oral Dose in Healthy Male Subjects).

Lixosicone (AEF0117, 3β-(4-methoxybenzyloxy)pregn-5-en-20-one) is a compound derived from pregnenolone by Aelis Farma, which acts as a biased negative allosteric modulator of the cannabinoid CB₁ receptor, representing a new class of compounds referred to as CB₁-selective signalling-specific inhibitors (CB₁-SSi). It binds to an allosteric site on the CB₁ receptor and modifies the downstream signalling produced as a result of CB₁ activation, preventing CB₁ mediated changes to mitogen-activated protein kinase (MAPK) phosphorylation but without affecting the signalling mediated by cyclic AMP. Unlike pregnenolone, AEF0117 is specific for the CB₁-SSi activity and lacks the neurosteroid action typical of many structurally related compounds.^[1]

In Phase II human clinical trials in patients diagnosed with cannabis use disorder, AEF0117 was found to partly but not completely block the effects of THC, and reduced cannabis self-administration but without producing an acute withdrawal syndrome and with relatively mild side effects. It is hoped that compounds of this type may be useful either as medications for the treatment of cannabinoid dependence, or could be used alongside medicinal cannabis to reduce unwanted side effects while retaining therapeutic efficacy.^[2]

As of March 2026, lixosicone is in phase 2 clinical trials for treatment of substance-related disorders.^[3] It is being developed by Aelis Farma.^[3]

Clinical Development

The compound has shown promising results in clinical settings:

• Phase 2a results: In clinical trials evaluated by the National Institute on Drug Abuse, lixosicone significantly reduced the positive subjective effects ("the high") of cannabis by 19% at lower doses and up to 38% at higher doses compared to a placebo.
• Reduced consumption: Testing demonstrated that the drug successfully reduced cannabis self-administration.
• Safety profile: Across early-stage evaluations, the drug was found to be safe, well-tolerated, and did not precipitate adverse behavioral withdrawal symptoms

SYN

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=98A554C6AEFBBFD20722462022415D6C.wapp1nA?docId=US402829323&_cid=P10-MQRGET-66134-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN309682512&_cid=P10-MQRGHV-67541-1

Stage 1: Compound of formula (IV): (3S,8S,9S,10R,13S,14S,17S)-10,13-dimethyl-17-(2-methyl) (-1,3-dioxane-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadiene Preparation of [a]phenanthrene-3-ol

Phase 1 was carried out in batches. Ethylene glycol (11.676 kg), pregnenolone (6.992 kg), and p-toluenesulfonic acid (0.840 kg, 4.42 mol, 0.2 equivalents) were charged into the reactor. The reaction mixture was stirred at 15°C–25°C for 25 minutes. Triethyl orthoformate (20.939 kg) was added in three portions, and the mixture was stirred at 15°C–25°C for at least 1 hour. Once complete, the reaction mixture was collected and slowly poured into a sodium bicarbonate solution (2.943 kg in 35.5 L of water) at 0°C–10°C. At the end of the addition, the reaction mixture was stirred at 0°C–10°C for 1 hour, then filtered and washed with water (12 L). The filtrate was also washed with 2-propanol (12 L) and dried under vacuum under a nitrogen stream. The dried solids were collected and charged into the reactor with 2-propanol (35 L). The slurry was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and stirred at room temperature for 12 hours. The reaction mixture was then cooled to between 0°C and 10°C and stirred for 2 hours. The solid was filtered and washed with 2-propanol (12 l), and then dried under vacuum under a nitrogen stream. Compound (IV) (8.031 kg) was obtained in a yield of 100.8% (uncorrected yield).

Phase 2: Compound of formula (II): 2-(3S,8S,9S,10R,13S,14S,17S)-3-((4-methoxybenzyl)oxy (10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1-H-cyclopentadien[a]) Preparation of phenanthrene-17-yl)-2-methyl-1,3-dioxolane

Compound (IV) (3.460 kg) and tetrahydrofuran (THF) (69 l) were charged into a reactor. The reaction mixture was stirred at 20°C–25°C for 80 minutes. The reaction mixture was filtered, and the solution of compound (IV) in THF was charged into the reactor. t-BuOK (2.835 kg) was added in portions to the THF solution of compound (IV) at 20°C–25°C. At the end of the addition, p-methoxybenzyl chloride (2.832 kg) and THF (4 l) of formula (III) were added to the reaction mixture via a feeding funnel. The reaction mixture was heated at 38°C–42°C. TBAI (1.555 kg) was added in portions to the reaction mixture at 38°C–42°C. The reaction mixture was heated at 55°C–60°C for 16 hours and 30 minutes.

Once complete, the reaction mixture is concentrated under vacuum to distill off 34-36 l of THF. The reaction mixture is then cooled to room temperature. Water (52 l) is added to the reactor, which is then cooled to 0-10 °C. The reaction mixture is carefully poured onto the water while maintaining the temperature at 0-10 °C. At the end of the addition, the reaction mixture is stirred at 0-10 °C for 1 hour and 50 minutes. The reaction mixture is filtered and washed with water (13 l). The filtrate is washed with acetonitrile (13.5 l), and the solids are dried under vacuum for 4 days under a nitrogen stream.

The solid was collected and acetonitrile (13 L) was added to the reactor. The mixture was heated under reflux for 4 hours. An additional acetonitrile (11 L) was added to the reactor and heated under reflux until a clear solution was obtained. The reaction mixture was cooled to room temperature and stirred at room temperature for 14 hours. The reaction mixture was cooled to 0 °C–10 °C and stirred at 0 °C–10 °C for 45 minutes, then filtered. Acetonitrile (10.5 L) was added to the reactor, cooled to 0 °C–10 °C, and then added to the filter to wash the filtrate. The solid was dried under vacuum under a nitrogen stream for 21 hours. Compound (II) (2.449 kg) was obtained in a yield of 59.2%.

• Stage 3: Preparation of compound (I): 3pMBP

Compound (II) (2.448 kg) and dichloromethane (10 L) were charged into a reactor. The solution was stirred for 20 minutes. 1 M hydrochloric acid (4.9 L) was added to the solution at 15 °C–25 °C. The reaction mixture was stirred until complete at 15 °C–25 °C. Dichloromethane (8 L) was added (to completely dissolve any precipitate) and phase separation was allowed. The organic layer was washed twice with water (5 L). The organic layer was collected and 2-propanol (24.5 L) was charged into a reactor at 15 °C–25 °C. The reaction mixture was concentrated under vacuum at a temperature below 40 °C. After completion, the reaction mixture was heated to reflux. 2-propanol (40 L) was added until a clear solution was observed. The reaction mixture was cooled to room temperature and stirred at room temperature for 12 hours. The reaction mixture was cooled to 0 °C–10 °C and stirred at 0 °C–-10 °C for 1 hour. The solid was filtered and washed with 2-propanol (5 l), then dried under vacuum with a nitrogen flow rate while the filter was heated at 35 °C–45 °C for 20 hours. Compound (I) was obtained in 85.8% yield (1.907 kg).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019162328&_cid=P10-MQRGHV-67541-1

PAT

• 3β-(4-Methoxybenzyloxy)pregnant-5-en-20-one for the treatment of cannabinoid-related disordersPublication Number: CN-111757740-BPriority Date: 2018-02-20Grant Date: 2023-12-15
• 3beta-(4-methoxybenzyloxy)paragan-5-en-20-one for use in the treatment of cannabinoid-related disordersPublication Number: IL-276697-B2Priority Date: 2018-02-20
• 3-BETA-(4-METHOXYBENZYLOXY)PREGN-5-EN-20-ONE FOR USE IN THE TREATMENT OF CANNABINOID-RELATED DISORDERSPublication Number: PT-3755339-TPriority Date: 2018-02-20
• 3beta-(4-methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of Cannabinoids-Related DisordersPublication Number: US-2023226076-A1Priority Date: 2018-02-20
• 3beta-(4-methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of cannabinoids-related disordersPublication Number: EP-3755339-A1Priority Date: 2018-02-20
• 3beta-(4-methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of Cannabinoids-Related DisordersPublication Number: US-2021030768-A1Priority Date: 2018-02-20
• 3-beta-(4-methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of cannabinoids-related disordersPublication Number: EP-3755339-B1Priority Date: 2018-02-20Grant Date: 2024-01-03
• 3BETA-(4-METHOXYBENZYLOXY)PREGN-5-EN-20-ONE FOR USE IN THE TREATMENT OF CANNABINOIDS RELATED DISORDERSPublication Number: MA-51891-B1Priority Date: 2018-02-20
• 3Beta-(4-Methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of cannabinoid-related disordersPublication Number: MD-3755339-T2Priority Date: 2018-02-20
• 3-BETA-(4-METHOXYBENZYLLOXY)PREGN-5-EN-20-ONE FOR USE IN THE TREATMENT OF CANNABINOID-RELATED DISORDERSPublication Number: HR-P20240276-T1Priority Date: 2018-02-20
• 3beta-(4-methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of cannabinoids-related disordersPublication Number: WO-2019162328-A1Priority Date: 2018-02-20
• 3BETA-(4-METHOXYBENCYLOXY)PREGN-5-EN-20-ONE FOR USE IN THE TREATMENT OF CANNABINOID-RELATED DISORDERS.Publication Number: MX-2020008687-APriority Date: 2018-02-20
• 3β-(4-methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of cannabinoids-related disordersPublication Number: US-11484537-B2Priority Date: 2018-02-20Grant Date: 2022-11-01
• 3beta-(4-methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of cannabinoids-related disordersPublication Number: AU-2019223049-A1Priority Date: 2018-02-20
• 3beta-(4-methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of cannabinoids-related disordersPublication Number: CA-3090975-A1Priority Date: 2018-02-20

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References

 "AEF 0117". AdisInsight. 13 March 2026. Retrieved 17 April 2026.

 US 11484537, Piazza PV, Fabre S, Metna M, Monlezun S, Busquet-Garcia A, Cota D, Marsicano G, Revest JM, Vallée M, "3β-(4-methoxybenzyloxy)pregn-5-en-20-one for use in the treatment of cannabinoids-related disorders.", issued 1 November 2022, assigned to Universite de Bordeaux.

 Haney M, Vallée M, Fabre S, Collins Reed S, Zanese M, Campistron G, et al. (June 2023). "Signaling-specific inhibition of the CB₁ receptor for cannabis use disorder: phase 1 and phase 2a randomized trials". Nature Medicine. 29 (6): 1487–1499. doi:10.1038/s41591-023-02381-w. PMC 10287566. PMID 37291212.

Clinical data
Other names	AEF0117; AEF-0117; 3β-(4-Methoxybenzyloxy)pregn-5-en-20-one
Drug class	Cannabinoid CB1 receptor negative allosteric modulator
Identifiers
IUPAC name
CAS Number	1610878-71-1
PubChem CID	139433957
ChemSpider	129421614
Chemical and physical data
Formula	C29H40O3
Molar mass	436.636 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

//////////lixosicone, anax labs, cannabinoid CB1 receptor signalling inhibitor, AEF0117, AEF 0117, 9LG9CT78SV

#lixosicone, #anax labs, #cannabinoid CB1 receptor signalling inhibitor, #AEF0117, #AEF 0117, #9LG9CT78SV

Lomonitinib

 

Lomonitinib

CAS 2923221-56-9

MF C27H24N4O2 MW436.5 g/mol

3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[4,5-c]quinoline

• 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[4,3-c]quinoline
• 1H-Pyrazolo[4,3-c]quinoline, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydro-7-isoquinolinyl)-
• 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline
• 7-[3-(3,4-dimethoxyphenyl)-1H- pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4- tetrahydroisoquinoline
• 7-[3-(3,4-Dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline

3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline
tyrosine kinase inhibitor, antineoplastic, ZE46-0134, Eilean Therapeutics, U4DPU7W7QU

Lomonitinib (also known as ZE46-0134) is a highly potent, selective, orally bioavailable pan-FLT3 and IRAK4 small molecule inhibitor being developed for the treatment of Acute Myeloid Leukemia (AML). Developed by Eilean Therapeutics in collaboration with Expert Systems, it uniquely targets both primary mutations and the major drug-resistance pathways that cause other AML therapies to fail.

Mechanism of Action

Lomonitinib utilizes a dual-targeting framework to bypass conventional drug resistance:

• Pan-FLT3 Inhibition: It binds to and blocks FMS-like tyrosine kinase 3 (FLT3) mutations. This includes the challenging FLT3-ITD-F691L "gatekeeper" mutation, which typically confers resistance to all currently approved standard FLT3 inhibitors like gilteritinib.
• IRAK4 Inhibition: It simultaneously targets interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 activation acts as a key "escape pathway" that cancer cells use to survive and build adaptive resistance to standalone FLT3 therapy.

Key Clinical Advantages

According to preclinical models and clinical data presented at the American Society of Hematology (ASH), lomonitinib offers unique benefits:

• Superior Efficacy: In vivo models demonstrate stronger anti-tumor activity and deeper responses in gatekeeper mutation-dependent disease compared to gilteritinib.
• Favorable Loading Strategy: Because of its wide therapeutic index and low toxicity, clinicians can administer a high loading dose on Day 1 followed by a smaller maintenance dose. This achieves effective therapeutic drug levels by Day 4, a rapid target engagement not possible with older long-half-life FLT3 inhibitors.
• Low Drug Interactions: Clinical profiles show minimal pharmacokinetic interference from proton pump inhibitors (PPIs) or CYP3A4 inhibitors like itraconazole.

Development Status

Lomonitinib is currently classified as an investigational new drug:

1. Clinical Trials: It is undergoing open-label, dose-escalation Phase 1/1b trials in both Australia and the United States (such as trial NCT06366789) evaluating adults with FLT3-mutated relapsed or refractory AML.
2. Partnerships: The drug is being studied in the US in collaboration with The Leukemia & Lymphoma Society as part of their Beat AML master clinical trial portfolio

Lomonitinib is an orally bioavailable inhibitor of FMS-like tyrosine kinase 3 (FLT3; CD135; STK1; FLK2) mutations and interleukin-1 receptor-associated kinase 4 (IRAK4), with potential antineoplastic activity. Upon oral administration, lomonitinib targets, binds to and inhibits the activity of FLT3 mutations, including the FLT3-ITD-F691L gatekeeper mutation, while sparing the wild-type form of FLT3. This inhibits the proliferation of FLT3 mutant-expressing cancer cells. In addition, lomonitinib targets, binds to, and inhibits the kinase activity of IRAK4. This inhibits IRAK4-mediated signaling and may reduce adaptive resistance to FLT3 inhibition as toll-like receptor (TLR) activation plays an important role in resistance to FLT3 inhibition. FLT3, a class III receptor tyrosine kinase (RTK), is overexpressed or mutated in most B-lineage neoplasms and in acute myeloid leukemias. IRAK4, a serine/threonine-protein kinase, plays a key role in both the TLR and IL-1R signaling pathways.

• Dose Escalation and Expansion Study to Evaluate the Safety, PK, PD and Efficacy of ZE46-0134 in Adults With FLT3 Mutated or Spliceosome Mutated Relapsed or Refractory Acute Myeloid LeukemiaCTID: NCT06366789Phase: Phase 1Status: RecruitingDate: 2025-12-31
• Study of Biomarker-Based Treatment of Acute Myeloid LeukemiaCTID: NCT03013998Phase: Phase 1/Phase 2Status: RecruitingDate: 2025-12-17
• Study of Single and Multiple Ascending Doses of ZE46-0134 in Healthy VolunteersCTID: NCT06399315Phase: Phase 1Status: CompletedDate: 2025-12-09

SYN

US20250011319, Compound 1.31

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=A1EAFE0DBAFF71D8E655E689964CEA0E.wapp1nC?docId=WO2026080917&_cid=P12-MQUBN3-08111-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US445571045&_cid=P12-MQUBPX-10324-1

Example 34: 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.31)

A mixture of 3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline (P23) (153 mg, 0.5 mmol), tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.31.1) (172 mg, 0.55 mmol), K 2CO 3 (83 mg, 0.6 mmol), CuI (10 mg, 0.05 mmol), N,N-dimethylglycine (11 mg, 0.1 mmol), and DMAA (2 mL) was stirred under Ar at 145° C. for 72 h, cooled to ambient temperature, diluted with CHCl 3, washed with 1% aq. solution of Na 2EDTA, and concentrated under reduced pressure. The residue was subjected to HPLC to afford 87 mg (33%) of tert-Butyl 7-(3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.31.2). 1H NMR (400 MHz, DMSO-d 6): δ 9.57 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.77 (m, 1H), 7.69 (dd, J 1=8.0 Hz, J 2=1.6 Hz, 1H), 7.63 (s, 1H), 7.57 (m, 3H), 7.51 (m, 2H), 7.17 (d, J=8.4 Hz, 1H), 4.63 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.68 (m, 2H), 2.98 (m, 2H), 1.45 (s, 9H). LCMS (ESI) m/z 538 [MH] +.

To a solution of 1.31.2 (45 mg, 0.084 mmol) in dioxane (2 mL) was added 3N solution of HCl in dioxane (2 mL), and the mixture was stirred for 4 h at ambient temperature. The formed precipitate was filtered off, washed with ether, and dried under reduced pressure at 50° C. to afford 40 mg (78%) of the title compound 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.31). 1H NMR (400 MHz, DMSO-d 6): δ 9.93 (s, 1H), 9.80 (brs, 2H), 8.50 (d, J=8.4 Hz, 1H), 8.01 (t, J=7.6 Hz, 1H), 7.74 (m, 4H), 7.59-7.66 (m, 3H), 7.20 (d, J=7.6 Hz, 1H), 4.40 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.49 (m, 2H), 3.23 (t, J=6.0 Hz, 2H).

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References

• Substituted 1H-pyrazolo [4,3-c ] quinolines, methods of preparation and uses thereofPublication Number: CN-118076605-APriority Date: 2021-10-15
• SUBSTITUTED 1H-PYRAZOLO [4,3-c] QUINOLINES, METHODS OF PREPARATION, AND USE THEREOFPublication Number: US-2025011319-A1Priority Date: 2021-10-15

////////lomonitinib, anax labs, tyrosine kinase inhibitor, antineoplastic, ZE46-0134, Eilean Therapeutics, U4DPU7W7QU

#lomonitinib, #anax labs, #tyrosine kinase inhibitor, #antineoplastic, #ZE46-0134, #Eilean Therapeutics, #U4DPU7W7QU

LONITOCLAX

 

Lonitoclax

CAS 2952589-57-8

MF C43H45ClN4O5 MW733.3 g/mol

5-[5-chloro-2-[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-(4-hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethylpyrrole-3-carboxamide

• 1H-Pyrrole-3-carboxamide, 5-[5-chloro-2-[[(3S)-3,4-dihydro-3-(4-morpholinylmethyl)-2(1H)-isoquinolinyl]carbonyl]phenyl]-N-(4-hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethyl-
• 5-(5-Chloro-2-(((3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2-(1-H)-yl)carbonyl)phenyl)-N-4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide
• 5-[5-chloro-2-[(3S)-3-(morpholinomethyl)- 3,4-dihydro-1H-isoquinoline-2- carbonyl]phenyl]-N-(4-hydroxyphenyl)-N- [(3-methoxy-2-methyl-phenyl)methyl]-1,2- dimethyl-pyrrole-3-carboxamide
• 5-{5-Chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide

5-(5-chloro-2-{(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl}phenyl)-N-(4-
hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide
B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, ZE50-0134, ZE50 0134, Lomond Therapeutics, CANCER, 76NBC3X6A3

Lonitoclax (also known as ZE50-0134) is an investigational, next-generation, orally administered B-cell lymphoma 2 (Bcl-2) inhibitor being developed for the treatment of hematologic malignancies like Acute Myeloid Leukemia (AML) and Chronic Lymphocytic Leukemia (CLL). Developed by Lomond Therapeutics, the drug is engineered as a highly selective option to improve upon existing first-generation Bcl-2 inhibitors like venetoclax.

Mechanism and Advantages Over Venetoclax

Unlike earlier therapies, lonitoclax features a unique binding mode and a structurally distinct chemotype. Its design yields several pharmacology advantages:

• Higher Selectivity: It binds tightly to Bcl-2 while demonstrating exceptional selectivity over Bcl-xL, which helps lower hematologic toxicities.
• Limited Immune Suppression: In preclinical data, lonitoclax spared healthy non-malignant immune cells (B cells, CD8 T cells, and NK cells), a major shift from the immunosuppressive profile of venetoclax.
• Reduced Drug Interaction & Accumulation: It features a shorter half-life (~9–10 hours) and minimal CYP3A4 (P4503A4) inhibition. This prevents the drug from building up dangerously and mitigates the risk of Tumor Lysis Syndrome (TLS), potentially enabling safer outpatient treatments.

Clinical Development Status

Lonitoclax is currently advancing through early-phase clinical trials:

• IND Clearances: The U.S. FDA cleared Investigational New Drug (IND) applications evaluating lonitoclax for CLL/SLL and as a combination treatment for relapsed or refractory AML.
• Healthy Volunteer Studies: Phase 1 single ascending dose (SAD) studies in healthy adults confirmed that the drug is well tolerated with linear pharmacokinetics and no significant safety issues. Target engagement was confirmed through plasma apoptosis assays.
• Combination Trials: Active Phase 1b multicenter trials are underway evaluating the safety, efficacy, and synergy of lonitoclax when combined with hypomethylating agents like azacitidine in AML patients.

SYN

US20250115577, Compound 7

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023129553&_cid=P11-MQVQMH-93381-1

ADVERISEMENT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

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References

• Bcl-2 inhibitorsPublication Number: WO-2023129553-A1Priority Date: 2021-12-29
• BCL-2 InhibitorsPublication Number: US-2025115577-A1Priority Date: 2021-12-29
• Bcl-2 inhibitorsPublication Number: EP-4457223-A1Priority Date: 2021-12-29

///////Lonitoclax, ANAX LABS, B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, ZE50-0134, ZE50 0134, Lomond Therapeutics, CANCER, 76NBC3X6A3

#Lonitoclax, #ANAX LABS, #B-cell lymphoma 2 (Bcl-2) inhibitor, #antineoplastic, #ZE50-0134, #ZE50 0134, #Lomond Therapeutics, #CANCER, #76NBC3X6A3