Bivamelagon

Bivamelagon

CAS 2641595-54-0

NO1Y8WRA8N, 629.3 g/mol, C₃₅H₅₃ClN₄O₄

MC-4R Agonist 2

• N-[(3S,5S)-1-[[(3S,4R)-4-(4-Chlorophenyl)-1-(1,1-dimethylethyl)-3-pyrrolidinyl]carbonyl]-5-(4-morpholinylcarbonyl)-3-pyrrolidinyl]-2-methyl-N-(cis-4-methylcyclohexyl)propanamide
• N-((3S,5S)-1-((3S,4R)-1-(tert-Butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-(cis-4-methylcyclohexyl)isobutyramide
• N-[(3S,5S)-1-[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidine-3-carbonyl]-5-(morpholine-4-carbonyl)pyrrolidin-3-yl]-2-methyl-N-(4-methylcyclohexyl)propanamide

LB54640; LB-54640; LR-19021; LR19021

MC-4R Agonist 2 (Example 1) is a MC4R agonist. MC-4R Agonist 2 can be used in the study of obesity, diabetes, inflammation, and erectile dysfunction^[1].

SCHEME

PATENT

WO2021091283A1.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021091283&_cid=P21-M9NZN0-90342-1

Step D: Preparation of N -((3 S ,5 S )-1-((3 S ,4 R )-1-( tert -butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)- N -((1 s ,4 R )-4-methylcyclohexyl)isobutyramide hydrochloride

[173]

 N -((3  S ,5  S )-1-((3  S ,4  R )-1-(  tert -butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-  N -((1  s ,4  R )-4-methylcyclohexyl)isobutyramide (5.0 g, 7.95 mmol) obtained in Step C was dissolved in ethyl acetate (50 ml), and a 2N hydrochloric acid ethyl acetate solution (3.97 ml, 15.89 mmol) was slowly added. After stirring at room temperature for 30 minutes, the reaction solvent was concentrated under reduced pressure. The resulting crude solid was purified by trituration using hexane and diethyl ether to obtain the title compound (5.23 g, 99%).

[174]

MS [M+H] = 630 (M+1)

[175]

¹H NMR (500 MHz, CD ₃OD) δ 7.49-7.44 (m, 4H), 4.83 (m, 1H), 4.23-4.20 (m, 1H), 3.95-3.91 (m, 2H), 3.79-3.47 (m, 14H), 3.03-3.00 (m, 1H), 2.86-2.82 (m, 1H), 2.73-2.67 (m, 1H), 2.20-2.14 (m, 1H), 1.97 (m, 1H), 1.80-1.62 (m, 5H), 1.50 (s, 9H), 1.44-1.27 (m, 3H), 1.06-1.04 (m, 9H)

PATENT

WO2022235103

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022235103&_cid=P21-M9NZHZ-87240-1

Preparation of cyclohexyl-3-carbonyl-l)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide (MC70)

[141]

[142]The title compound was obtained through the following steps A, B, and C. 

[143]

Step A: Preparation of methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate

[144]Methyl (2S,4S)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate hydrochloride (28.7 g, 82.73 mmol) obtained in Manufacturing Example 1, (3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (24.5 g, 86.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.2 g, 115.83 mmol) and 1-hydroxybenzotriazole hydrate (15.7 g, 115.83 mmol) obtained in Manufacturing Example 2 were dissolved in N,N’-dimethylformamide (400 ml) and N,N’-diisopropylethylamine (72.0 ml, 413.66 mmol) was slowly added. The mixture was stirred at room temperature for 16 hours and the reaction solvent was concentrated under reduced pressure. A 0.5 N aqueous sodium hydroxide solution was added, and extraction was performed twice with ethyl acetate. The organic layer was washed twice with an aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate (41.19 g, 87%). 

[145]

MS [M+H] = 575 (M+1)

[146]

Step B: Preparation of (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid

[147]Methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate (39.4 g, 68.62 mmol) obtained in the above step A was dissolved in methanol (450 ml), and 6N sodium hydroxide aqueous solution (57.2 ml, 343.09 mmol) was added. The mixture was stirred at room temperature for 16 hours, and the pH was adjusted to about 5 with 6N hydrochloric acid aqueous solution, and then the reaction solution was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane, and the insoluble solid was filtered through a paper filter. The filtrate was concentrated under reduced pressure to obtain the crude title compound (38.4 g, 99%), which was used in the next step without purification. 

[148]

MS [M+H] = 561 (M+1)

[149]

Step C: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide

[150](2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid (38.4 g, 68.60 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.4 g, 96.04 mmol) and 1-hydroxybenzotriazole hydrate (13.0 g, 96.04 mmol) obtained in the above step B were dissolved in N,N’-dimethylformamide (200 ml), and then morpholine (5.9 ml, 68.80 mmol) and N,N’-diisopropylethylamine were sequentially added. (59.7 ml, 343.02 mmol) was slowly added. The mixture was stirred at room temperature for 16 hours and the reaction solution was concentrated under reduced pressure, 0.5 N aqueous sodium hydroxide solution was added, and extraction was performed twice with ethyl acetate. The organic layer was washed twice with aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide (37.05 g, 86%,  

MC70  ). 

[151]

MS [M+H] = 630 (M+1)

Bivamelagon (INNTooltip International Nonproprietary Name; developmental code names LB54640, LR-19021) is a small-molecule melanocortin MC₄ receptor agonist under development by LG Chem Life Sciences for the treatment of hypothalamic obesity, .^[1][2] Unlike the older drug with the same mechanism of action, setmelanotide, it can be taken orally.^[3][4][5] As of March 2024, it is in phase 2 clinical trials.^[1]

References

1. ^ Jump up to:^a b “Rhythm Pharmaceuticals”. AdisInsight. 13 March 2024. Retrieved 25 February 2025.
2. ^ “Delving into the Latest Updates on Bivamelagon with Synapse”. Synapse. 23 January 2025. Retrieved 25 February 2025.
3. ^ Aronne, Sarah R. Barenbaum, Louis J. (2023). “Antiobesity Medications on the Horizon”. Handbook of Obesity – Volume 2 (5 ed.). CRC Press. pp. 394–401. doi:10.1201/9781003432807-42. ISBN 978-1-003-43280-7.
4. ^ First-in-Human Study of Safety, Pharmacodynamics of LB54640, An Oral Melanocortin-4 Receptor Agonist Mirza, Victoria, MD, MPH; Lee, Jisoo, MD; Gwak, Heemin; Yang, Yunjeong; Kim, Mina.  Obesity; Silver Spring Vol. 30, (Nov 2022): 145-146.
5. ^ Piper, Noah B.C.; Whitfield, Emily A.; Stewart, Gregory D.; Xu, Xiaomeng; Furness, Sebastian G.B. (August 2022). “Targeting appetite and satiety in diabetes and obesity, via G protein-coupled receptors”. Biochemical Pharmacology. 202: 115115. doi:10.1016/j.bcp.2022.115115. PMID 35671790. S2CID 249452717.

[1]. Seung Wan Kang, et al. Melanocortin-4 receptor agonists. Patent WO2021091283A1.

////////Bivamelagon, LB54640, LB-54640, LR-19021, LR19021, NO1Y8WRA8N