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Balomenib (also known as ZE63-0302) is an oral, small-molecule menin inhibitor currently in clinical development for metabolic and oncological conditions. It works by disrupting the protein-protein interaction between menin and KMT2A (formerly MLL), a mechanism that plays a critical role in both pancreatic beta-cell function and certain types of leukemia.
Key Therapeutic Areas
Type 2 Diabetes (T2D): Balomenib is being investigated as a potentially disease-modifying treatment to improve pancreatic beta-cell function and survival. As of late 2025, it has advanced into Phase 1b clinical trials specifically for adults with T2D to evaluate its effects on fasting glucose, insulin dynamics, and HbA1c.
Oncology (AML): It is also a candidate for treating acute myeloid leukemia (AML) with KMT2A rearrangements or NPM1 mutations. Preclinical data suggests it may be more effective against resistance mutations than earlier menin inhibitors.
Development and Safety
Corporate Development: The drug was originally developed by Eilean Therapeutics. It is now the lead program for Clywedog Therapeutics, which is merging with Barinthus Biotherapeutics to focus on metabolic diseases.
Safety Profile: Early trial results indicate a favorable safety profile. Notably, it was designed to minimize QTc prolongation (heart rhythm issues), a side effect common in other menin inhibitors.
Сlinical Study Aiming to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of ZE63-0302 in Healthy VolunteersCTID: NCT06780124Phase: Phase 1Status: CompletedDate: 2026-01-22
Study to Assess Safety, Tolerability, PK, and PD of Multiple Doses of ZE63-0302 Administrated Orally in T2DM Patients.CTID: NCT07234864Phase: Phase 1Status: RecruitingDate: 2026-01-22
Example 46. 4-Methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (Compound 102)
Compound was prepared using procedure described in the Example 45 and 5-formyl-4-methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-1H-indole-2-carbonitrile P177 instead of 5-formyl-4-methyl-1-{[(2R)-5-oxomorpholin-2-yl]methyl}-1H-indole-2-carbonitrile P176. Compound 102 was obtained with yield 49%. 1H NMR (400 MHz, DMSO-d 6), δ: 8.46 (s, 1H), 7.99 (m, 2H), 7.73 (m, 2H), 7.52 (m, 1H), 7.46 (d, J=5.6 Hz, 1H), 7.31 (d, J=4.8 Hz, 1H), 4.54 (m, 1H), 4.20 (m, 2H), 4.05 (m, 1H), 3.90 (m, 4H), 3.52 (m, 2H), 3.35 (m, 1H), 3.17 (m, 1H), 2.39 (m, 2H), 1.79 (m, 4H). LCMS (ESI) [MH] +: 618.
Example 46. 4-Methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (Compound 102)
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Becondogrel is an antiplatelet medication and an irreversible P2Y12 receptor antagonist. It is chemically known as 2-oxoclopidogrel, which is a direct metabolic intermediate of the widely used drug clopidogrel (Plavix).
Key Characteristics
Mechanism of Action: It prevents blood cells (platelets) from sticking together, which helps inhibit the formation of blood clots (thrombosis).
Relationship to Clopidogrel: Standard clopidogrel is a prodrug that requires two metabolic steps in the liver to become active. Becondogrel is designed to bypass the first of these steps, potentially reducing the individual variability in effectiveness seen with clopidogrel due to genetic differences in liver enzymes (CYP450).
Clinical Status: As of early 2025, becondogrel was included in the World Health Organization's (WHO) proposed International Nonproprietary Name (INN) list, indicating its development for medical use
[0042] 58.1 g (0.15 mol) of (R)-methyl 2-(2-chlorophenyl)-2-(4-nitrophenylsulfonyloxy)-acetate (II-1), 32.3 g (0.17 mol) of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one hydrochloride (III-1), and 37.8g (0.38 mol) of potassium bicarbonate were added to 500 ml of acetonitrile. The reaction was stirred under a nitrogen atmosphere at room temperature for 26 hrs. The reaction solution was allowed to stand and the insoluble material was filtered off, to obtain a dark red mother liquor. The solvent was evaporated under reduced pressure, and 35.4 g of an oil product was obtained after purification by flash column chromatography (petroleum ether:ethyl acetate = 4:1). Yield 70%. Recrystalization from ethanol afforded 18.1 g of a pure product (IV-1) as a white solid. mp: 146-148°C, ee = 97.5%, [α] D19 = +114.0° (c 0.5, MeOH); 1H-NMR (300 MHz, CDCl 3) δ 1.79-1.93 (m, 1 H), 2.30-2.40 (m, 1 H), 2.56-2.70 (m, 1 H), 3.00-3.27 (m, 2 H), 3.72 (s, 3 H), 3.79-3.93 (m, 1 H), 4.12-4.19 (m, 1 H), 4.89 (d, 1 H, J= 5.6 Hz), 6.00 (d, 1 H, J = 5.2 Hz), 7.26-7.50 (m, 4 H); 13C-NMR (75 MHz, CDCl 3) δ 33.9, 34.0, 49.0, 49.7, 51.1, 51.6, 52.2, 52.4, 67.3, 76.6, 77.0, 77.4, 126.6, 126.8, 127.2, 129.8, 130.1, 132.7, 134.8, 167.2, 167.4, 170.8, 198.6; ESI-MS m/ z 338.1 [M+H] +; HRMS Calcd for C 16H 17NO 3SCl [M+H] +m/ z 338.0618, found 338.0626.
. The chemical name of the compound with the Equation I structure is: (S)-2-(2-chlorophenyl)-2-((S)-2-oxo-2,6,7,7a-tetrahydrothiophene[3,2-c]and pyridine-5(4H))yl)methyl acetate.
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(1R,5R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexane muscarinic receptor agonist, ML 007, MPL 0527, 5UXW4B47R9
Betovumeline (also known as ML-007 or MPL-0527) is a muscarinic receptor agonist currently being developed for the treatment of neurological and neuropsychiatric disorders.
It is specifically designed to target muscarinic receptors in the brain, which play a critical role in cognitive and motor functions.
Key Characteristics
Mechanism of Action: It acts as an agonist for muscarinic acetylcholine receptors (mAChR).
Research Focus: It is primarily being investigated for its potential in treating neurological disorders, such as schizophrenia or Alzheimer's disease-related cognitive impairment.
Chemical Detail: Its chemical structure is (1R,5R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclohexane.
Development Stage: It is an investigational drug, meaning it is currently for research use only and has not yet been approved for general medical or human use.
Birelentinib (also known as DZD8586) is a first-in-class, non-covalent dual inhibitor of LYN (lymphocyte-specific protein tyrosine kinase) and BTK (Bruton's tyrosine kinase).
It is currently being developed by Dizal Pharmaceutical as an oral therapy for various B-cell malignancies.
Clinical Status and FDA Designations
As of late 2025, birelentinib has received significant attention for its potential in treating resistant blood cancers:
Fast Track Designation: In August 2025, the U.S. FDA granted Fast Track designation to birelentinib for adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Target Population: It is specifically intended for those who have failed at least two prior therapies, including a covalent BTK inhibitor and a BCL-2 inhibitor.
Key Trials: It is being evaluated in multiple studies, including the Phase 3 Tai-Shan6 trial comparing it against standard treatments like bendamustine and rituximab.
Unique Therapeutic Properties
Birelentinib is designed to overcome common drug resistance mechanisms found in existing treatments:
Overcoming Resistance: It targets both BTK-dependent pathways (including the common C481X mutation) and BTK-independent B-cell receptor (BCR) signaling pathways.
Blood-Brain Barrier (BBB) Penetration: A notable feature is its ability to fully penetrate the blood-brain barrier, which may offer therapeutic benefits for patients with central nervous system (CNS) involvement.
Efficacy: Early Phase 1/2 data presented at the ASH Annual Meeting and EHA Congress in 2025 showed an Objective Response Rate (ORR) of 84.2% in heavily pretreated patients
Birelentinib is an orally bioavailable non-covalent dual inhibitor of tyrosine-protein kinases Lyn (LYN) and BTK (Bruton's tyrosine kinase; Bruton agammaglobulinemia tyrosine kinase), with potential antineoplastic activity. Upon oral administration, birelentinib targets and inhibits both LYN and BTK, thereby blocking both BTK-dependent and BTK-independent B-cell antigen receptor (BCR) signaling pathways. This prevents the proliferation of malignant B-cells in which the BCR signaling pathway is overactivated. Birelentinib is able to cross the blood-brain barrier (BBB) and thus potentially useful in the treatment of central nervous system (CNS) metastases
Blixeprodil shows antidepressant-like effects in rodents.[3][11][4][9] It appears to have a greater separation between antidepressant-like and ataxia-inducing doses than ketamine in rodents and hence might have better tolerability.[3][7][9] Whereas ketamine shows only 3-fold separation between antidepressant-like and ataxic doses, there was 13-fold separation for blixeprodil, and it did not produce hyperlocomotion at doses >20-fold higher than the minimum antidepressant-like dose.[9] In relation to the preceding, blixeprodil is claimed to be non-dissociative at therapeutic doses.[2][4] However, dissociative and other related effects have been observed at low incidences and at higher doses.[4]
The drug is a close analogue of ketamine, with a 4-fluorogroup instead of a 2-chloro group on the phenyl ring and in (2R)-enantiopure form.[12] Hence, blixeprodil is related to arketamine ((R)-ketamine); it is said to "bet" on the notion that arketamine is importantly involved in the antidepressant effects of ketamine, in spite of arketamine having less propensity for inducing dissociation.[13]
Example 15: Preparation of Compounds 117rac and 18rac
Step 1: Preparation of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one
[0364] A mixture of 2-(4-fluorophenyl)cyclohexan-1-one (5 g, 26.01 mmol, 1 eq), ceric ammonium nitrate (CAN, 28.52 g, 52.02 mmol, 2 eq), and Cu(OAc)2 (945 mg, 5.20 mmol, 0.2 eq) in DCE (50 mL) was stirred at 85 °C for 12 hrs. The mixture was cooled, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 0/1) to afford 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (2.5 g, 10.54 mmol, 40.52% yield) as a yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.47 - 7.29 (m, 2H), 7.22 - 7.04 (m, 2H), 3.12 (ddd, J = 3.6, 10.0, 14.0 Hz, 1H), 2.86 - 2.76 (m, 1H), 2.75 - 2.62 (m, 1H), 2.61 - 2.47 (m, 1H), 2.08 - 1.86 (m, 3H), 1.80 (dt, J = 3.6, 9.2 Hz, 1H).
Step 2: Preparation of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (117rac)
[0365] A mixture of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (3 g, 12.65 mmol, 1 eq) and Zn (19.85 g, 303.51 mmol, 24 eq) in AcOH (25 mL) was stirred at 20 °C for 12 hrs. The mixture was cooled, filtered, and concentrated. The residue was dissolved in DCM, washed with sat.
NaHCO3, H2O, and brine, dried over Na2SO4, filtered, and concentrated. The residue was
Step 3: Preparation of 2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (18rac)
[0366] A mixture of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1.3 g, 6.27 mmol, 1 eq) and methyl trifluoromethanesulfonate (1.03 g, 6.27 mmol, 1 eq) in hexafluoroisopropanol (HFIP, 130 mL) was stirred at 0 - 25 °C for 12 hrs under N2 atmosphere. The mixture was filtered and concentrated. The residue was adjusted to pH = 7 with sat. Na2CO3 (20 ml). The aqueous phase was extracted with EA (50 mL x 2). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Welch Xtimate C18250*70 mm, 10 μm; mobile phase: A: water(0.05% NH3H2O), B: ACN; B%: 18% - 48%, 32 min) to afford 2-(4-fluorophenyl)-2- (methylamino)cyclohexan-1-one (590 mg, 4.02 mmol, 42.45% yield) (18rac) as a white solid. LCMS (RT = 1.415 min, MS calc.: 221.12, [M+H]+ = 222.1); 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.26 - 7.17 (m, 2H), 7.07 (br t, J = 8.4 Hz, 2H), 2.92 - 2.74 (m, 1H), 2.50 - 2.26 (m, 3H), 2.12 - 1.93 (m, 4H), 1.90 - 1.63 (m, 4H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 211.15, 163.20, 160.75, 134.68, 134.65, 128.99, 128.91, 115.79, 115.58, 69.37, 39.70, 35.85, 28.87, 27.70, 22.21.
Example 1: Preparation of Compounds 1 and 2 and Their Enantiomers.
Step 1: Preparation of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one
[0110] A mixture of 2-(4-fluorophenyl)cyclohexan-1-one (14 g, 72.83 mmol, 1 eq), CAN (79.85 g, 145.66 mmol, 72.59 mL, 2 eq), and Cu(OAc)2 (2.65 g, 14.57 mmol, 0.2 eq) in DCE (140 mL) was stirred at 85 °C for 12 h. On completion, the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 0/1) to afford 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (6.1 g, 25.71 mmol, 35.31% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.41 - 7.31 (m, 2H), 7.16 (t, J=8.4 Hz, 2H), 3.11 (ddd, J=3.6, 10.4, 14.0 Hz, 1H), 2.87 - 2.76 (m, 1H), 2.73 - 2.64 (m, 1H), 2.60 -2.48 (m, 1H), 2.02 - 1.88 (m, 3H), 1.84 - 1.72 (m, 1H).
Step 2: Preparation of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1)
[0111] To a mixture of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (5.6 g, 23.61 mmol, 1 eq) in AcOH (10 mL) was added Zn (15.44 g, 236.06 mmol, 10 eq) in several portions and the resulting mixture was stirred at 30 °C for 12 h. On completion, the mixture was filtered and concentrated. The residue was dissolved in DCM (20 mL), washed with sat. aq. NaHCO3 (10 mL), H2O (5 mL), and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC (column: Agela DuraShell C18 (250 mm*80 mm, 10 μm); mobile phase: A: water (NH4HCO3), B: ACN; B%: 35%, 20 min) to afford 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (2.9 g, 13.99 mmol, 59.28% yield, 1) as a brown oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.52 - 7.40 (m, 2H), 7.32 (br s, 1H), 7.34 - 7.20 (m, 2H), 2.93 - 2.92 (m, 1H), 3.08 - 2.92 (m, 1H), 2.74 - 2.63 (m, 1H), 2.63 - 2.50 (m, 1H), 2.28 - 2.16 (m, 1H), 2.10 (br s, 2H), 2.04 - 1.85 (m, 4H).
Note: The free base of this compound is unstable and dimerizes over time. It should be stored frozen or quickly converted to the HCl salt to prevent this.
Step 3: Preparation of (S)-2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1S) and (R)-2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1R)
[0112] The racemate 1 (2.9 g) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in ETOH; B%: 27%, multi-injection process with 6-min spacing between injections) to afford ENT-1 free base (RT = 2.266 min, 1.1 g, 1.62 mmol, 1S_FB) as a yellow oil and ENT-2 free base (RT = 2.945 min, 1.1 g, 1.28 mmol, 1R_FB) as a yellow oil.
[0113] A portion of each free base was further purified by prep-HPLC (column: Welch Xtimate C18 (100 mm*25 mm, 3 μm); mobile phase: A: water (0.04% HCl), B: ACN; B%: 1% - 20%, 8 min) to afford ENT-1 HCl (RT = 2.266 min, 272 mg, HCl salt, 1S) as a white solid and ENT-2 HCl (RT = 2.945 min, 283 mg, HCl salt, 1R) as a white solid.
[0115] The retention times above, which identify the enantiomers, were determined using the free bases using the following chiral analytical method: column: Chiralpak AD-3 (150 mm×4.6 mm I.D., 3 μm); mobile phase: A: CO2 B: EtOH (0.1% IPAm, v/v); gradient (Time (min)/A%/B%): 0.0/90/10, 0.5/90/10, 3.5/50/50, 4.5/50/50, 5.0/90/10; flow rate: 2.5 mL/min; column temp.: 35 °C; ABPR: 2,000 psi.
Step 4: Preparation of (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (2S) and (R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (2R)
[0116] Compound 1S_FB (540 mg, 2.61 mmol, 1 eq) and methyl trifluoromethanesulfonate (427.59 mg, 2.61 mmol, 285.06 μL, 1 eq) were combined in hexafluoroisopropanol (40 mL) at 0
°C under N2 atmosphere and then the mixture was allowed to warm to 25 °C and stirred for 12 h. On completion, the residue was adjusted to pH 7 with sat. aq. Na2CO3 (10 mL) and the combined organic phase was washed with brine (100 mL * 2), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge C18 (150 mm*50 mm, 10μm); mobile phase: A: water (10 mM NH4HCO3), B: ACN; B%: 30% - 50%, 10 min) to afford 2S (260 mg, 1.18 mmol, 45.10% yield) as a white solid. Compound 2R was prepared by the same procedure starting from 1R_FB (590 mg, 2.85 mmol) in hexafluoroisopropanol (60 mL) (other quantities scaled based on molar equivalents) and obtained as an off-white solid (260 mg, 1.18 mmol, 41.27% yield).
"GM 1020". AdisInsight. 12 July 2024. Retrieved 20 February 2025.
Peplow M (June 2024). "Next-generation psychedelics: should new agents skip the trip?". Nature Biotechnology. 42 (6): 827–830. doi:10.1038/s41587-024-02285-1. PMID38831049. Other companies are confident that they can further reduce or even erase those effects without losing therapeutic efficacy. Gilgamesh, for example, is taking that approach with ketamine, DMT and psilocybin. In the case of ketamine, says Kruegel, the dissociative side effects require that the subjects remain under supervision. So Gilgamesh designed a ketamine analog called GM-1020 that has no dissociative effects (distortions in sight, sound and feelings of detachment) and that also has better oral bioavailability than ketamine itself. After completing a phase 1 trial last year, the company began dosing patients with GM-1020 in a phase 2 trial for major depressive disorder in March. "The hope is that the psychoactive effects will be limited enough that this can eventually be taken at home," says Kruegel.
Klein A, Dvorak D, Austin E, Marek G, Sporn J, Hughes Z, et al. (2023). "531. GM-1020 is a Novel, Orally Bioavailable NMDA Antagonist With Improved Separation Between Antidepressant and Ataxic Doses Compared to Ketamine". Biological Psychiatry. 93 (9): S308–S309. doi:10.1016/j.biopsych.2023.02.771.
Sá VL, de Jesus Santos G, da Fonseca Fraga I, da Silva JM, Santos, MG, et al. (2015). Avaliação farmacológica de um análogo a um antagonista do receptor N-Metil-D-Aspartato [Pharmacological evaluation of an analogue of an N-Methyl-D-Aspartate receptor antagonist] (PDF). I Congresso de Ciências Farmacêuticas do Interior Baiano. [Translated:] [...] ketamine has low oral availability and a narrow therapeutic index, generating adverse effects such as dissociation, cognitive impairment, sedation, and ataxia, which limits the acceptance of the drug in the treatment of depression. The preclinical characterization through in vitro and in vivo studies of GM-1020 ((R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one) may indicate a new therapy that presents bioavailability when administered orally and absence of undesirable motor effects.
