Atumelnant

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Atumelnant

CAS 2392970-97-5

MF C33H42F3N5O3 MW 613.7 g/mol

CRN04894, NR57FH6U1N

CRINETICS PHARMA, Orphan Drug Status, Congenital adrenal hyperplasia

N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide

N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-{(2R)-2-ethyl-4-[1-(trifluoromethyl) cyclobutane-1-carbonyl]piperazin-1-yl}pyridine-2-carboxamide
Adrenocorticotropic hormone receptor antagonist

  • OriginatorCrinetics Pharmaceuticals
  • ClassAmides; Antineoplastics; Antisecretories; Benzene derivatives; Cyclobutanes; Ethers; Fluorocarbons; Ketones; Piperazines; Pyridines; Quinuclidines; Small molecules
  • Mechanism of ActionMelanocortin type 2 receptor antagonists
  • Orphan Drug StatusYes – Congenital adrenal hyperplasia
  • Phase IICongenital adrenal hyperplasia; Cushing syndrome
  • No development reportedEctopic ACTH syndrome
  • 21 Aug 2025Atumelnant receives Orphan Drug status for Congenital adrenal hyperplasia in the US
  • 07 Aug 2025Crinetics pharmaceuticals plans phase II/III clinical trial for Cushing’s disease in 1H 2026
  • 08 May 2025Crinetics Pharmaceuticals plans the phase III CALM-CAH trial for Congenital adrenal hyperplasia (In adults) (PO), in the second half of 2025

Atumelnant (INNTooltip International Nonproprietary Name; developmental code name CRN04894) is an investigational new drug developed by Crinetics Pharmaceuticals for the treatment of adrenocorticotropic hormone (ACTH)-dependent endocrine disorders.[1] It is a selective antagonist of the melanocortin type 2 receptor (MC2R), also known as the ACTH receptor, which is primarily expressed in the adrenal glands.[1][2] The drug is orally active.[1] Atumelnant is being evaluated to treat conditions such as congenital adrenal hyperplasia (CAH) and ACTH-dependent Cushing’s syndrome caused for example by pituitary adenomas.[3]

Atumelnant is an orally bioavailable nonpeptide antagonist of the adrenocorticotropic hormone (ACTH) receptor (ACTHR; melanocortin receptor 2; MC2R), with potential steroid hormone production inhibitory activity. Upon oral administration, atumelnant competes with ACTH for receptor binding to MC2R in the adrenal cortex and inhibits ACTH signaling. This may inhibit the synthesis and secretion of steroid hormones. MC2R, a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors, plays a key role in adrenal steroidogenesis.

PAPER

Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist

Publication Name: ACS Medicinal Chemistry Letters

Publication Date: 2024-03-19, PMCID: PMC11017392, PMID: 38628803

DOI: 10.1021/acsmedchemlett.3c00514

PATENTS

SYN

compound 17h [PMID: 38628803]

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US278278493&_cid=P22-MFXDN2-76849-1

Example 31: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound 1-410)

Step 31-1, Preparation of 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxylic acid

      to a solution of 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid (450 mg, 0.98 mmol) from Example 25, step 3 in DCM (5.0 mL) was added TFA (1.14 mL, 14.8 mmol) at rt. The resulting solution was stirred at rt for 1 h and concentrated under vacuum to afford 6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylic acid. This residue was dissolved in ACN (2 mL) and neutralized with Et 3N (˜0.3 mL). The solution was used in the next HATU coupling step without further purification.
      To a solution of 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (332 mg, 1.98 mmol) in ACN (5 mL) was added HATU (751 mg, 1.98 mmol) and followed by Et 3N (0.26 mL, 1.98 mmol) at rt. After stirring at rt for 5 min, this HATU-activated solution was treated with the solution of 6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylic acid described above. The resulting mixture was stirred at rt for 30 min and concentrated under vacuum. The residue was purified by C18 reversed phase column chromatography to give the title compound (290 mg, 58% yield). LCMS (M+H) +=506.3.

Step 31-2, Preparation of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide

      to a solution of 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxylic acid (70 mg, 0.14 mmol) and HATU (58.0 mg, 0.15 mmol) in DMF (1.5 mL) was added Et 3N (0.074 mL, 0.55 mmol). After stirring at rt for 5 min, the resulting solution was treated with (S)-quinuclidin-3-amine dihydrochloride (33 mg, 0.17 mmol). The resulting mixture was stirred at rt for 1 hr and directly purified by C18 reversed phase column chromatography to give the title compound (40 mg, 47% yield). LCMS (M+H) +=614.3.

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References

  1.  “Crinetics Pharmaceuticals”. AdisInsight. 21 January 2025. Retrieved 25 February 2025.
  2.  “Atumelnant (CRN04894)”. crinetics.com. 14 August 2020.
  3.  Varlamov EV, Gheorghiu ML, Fleseriu M (December 2024). “Pharmacological management of pituitary adenomas – what is new on the horizon?”. Expert Opinion on Pharmacotherapy. 26 (2): 119–125. doi:10.1080/14656566.2024.2446625. PMID 39718553.
Clinical data
Other namesCRN04894
Routes of
administration		Oral[1]
Drug classMelanocortin MC2 receptor antagonist[1]
Identifiers
IUPAC name
CAS Number2392970-97-5
PubChem CID146361282
IUPHAR/BPS13339
ChemSpider129750231
UNIINR57FH6U1N
KEGGD13102
Chemical and physical data
FormulaC33H42F3N5O3
Molar mass613.726 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

////////Atumelnant, CRN04894, CRN 04894, NR57FH6U1N, CRINETICS PHARMA, Orphan Drug Status, Congenital adrenal hyperplasia, PHASE 3

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