Crinecerfont is an orally administered, nonsteroidal corticotropinreleasing factor type 1 (CRF1) receptor antagonista, sold under the brand name Crenessity, approved for medical use by the FDA in December 2024 for the treatment of classic congenital adrenal hyperplasia (CAH). By selectively inhibiting CRF1, Crinecerfont reduces excessive adrenocorticotropic hormone (ACTH) drive and lower the overproduction of adrenal androgens that is characteristic of CAH and it considers to be a first-in-class medicine.
Crinecerfont was developed by Neurocrine Biosciences, a San Diegobased biopharmaceutical company founded in 1992. Neurocrine specializes in discovering and developing treatments in neurology, endocrinology, and psychiatry. While Neurocrine has a history of multiple collaborations and compound in-licensing deals over the decades, Crinecerfont (NBI74788) can be described as an inhouse discovery or an internally led development from its broader CRF antagonist research programs, although Sanofi have also some patents on the synthesis of related substances. Neurocrine began its research into corticotropin-releasing factor type 1 receptor antagonists in the late 1990s and early 2000s. CRF1 antagonists were initially investigated for stress-related disorders (e.g., depression, anxiety, irritable bowel syndrome). Over time, researchers recognized that CRF1 antagonism could help reduce pituitary ACTH production and, in turn, help normalize adrenal steroid synthesis in CAH. This mechanistic insight led them to focus specifically on treating pediatric and adult classic CAH.
The originator patent where the synthesis of Crinecerfont is presented date from 2001 and was submitted by Sanofi-Synthelabo. The synthetic strategy goes through the formation of thee chiral center by using a chiral auxiliary during the reduction step. First, 4-Bromo-3-fluorotoluene (1) is converted into the Grignard derivative (2) with magnesium in boiling Et2O, and subsequently added to cyclopropylacetonitrile to produce ketone (3).
Condensation of 3 with hydroxylamine affords the oxime (4), which is further alkylated with benzyl bromide to yield the O-benzyl oxime (5). Asymmetric reduction of oxime (5) with borane in the presence of the aminoalcohol chiral auxiliary provides the (S)-amine intermediate (6). Reaction of amine (6) with ammonium thiocyanate and benzoyl chloride, followed by treatment with hydrazine hydrate, gives rise to the thiourea (7). Then, condensation of thiourea (7) with bromo ketone (8) in the presence of Et3N in boiling EtOH leads the aminothiazole (9), which upon alkylation of the amino group with propargyl bromide in the presence of NaH furnishes Crinecerfont. The intermediate bromo ketone (8) can be synthesized by Friedel-Crafts acylation of 4-chloro-2-methoxytoluene (10) with 2-bromopropionyl bromide employing AlCl3.
Alternatively, Neurocrine and Sanofi have published a patent (2021) on a different approach to the synthesis of the chiral amine intermediate, avoiding the use of chiral auxiliaries. Condensation of ketone (3) with (S)-phenylethylamine in the presence of p-toluene sulphonic acid in toluene at 115 °C provides imino compound 11, which is subjected to enantioselective hydrogenation over sponge nickel catalyst in toluene/EtOH and subsequent treatment with HCl to yield 2-cyclopropyl-1(S)-(3-fluoro-4-methylphenyl)ethanamine derivative (12). N-Debenzylation of intermediate (12) with H2 over Pd/C in MeOH at 60 °C, followed by treatment with aqueous NaOH in heptane produces free chiral amine 6, which upon cyclization with [2-(2-chloro-4-methoxy-5-methylphenyl)-1-methyl-2-oxoethyl]thiocyanate (13) in heptane at 85 °C leads to thiazole derivative (9). Following the same final step already shown in the prior scheme, Crinecerfont can be produced in good yields.
