Nirogacestat

Nirogacestat, sold under the brand name Ogsiveo, is an anti-cancer medication used for the treatment of desmoid tumors. It is a selective gamma secretase inhibitor that is taken by mouth. Nirogacestat was approved for medical use in the United States in November 2023. It is the first medication approved by the US Food and Drug Administration (FDA) for the treatment of desmoid tumors. The FDA considers it to be a first-in-class medication.

Medical uses Nirogacestat is indicated for adults with progressing desmoid tumors who require systemic treatment.

Adverse effects Nirogacestat treatment has been associated with several notable adverse effects across multiple studies. Hypophosphatemia is a significant and common side effect, with an incidence exceeding 40% in patients with various cancers including desmoid tumors, sarcoma, metastatic breast cancer, and solid organ cancers. Gastrointestinal toxicity is another concern, and glucocorticosteroid pretreatment and post-treatment regimens have shown efficacy in mitigating these effects in clinical trials. Reproductive toxicity has been observed in animal studies, with findings including ovarian atrophy, amenorrhea, premature menopause, reduced testes weight, and decreased sperm concentration and motility; some of these effects may be irreversible. There is a possible risk of non-melanoma skin cancer development. In vivo rat studies showed embryotoxicity, including decreased body weight, implantation loss and subcutis edema at doses lower than the recommended human dose. Additionally, there has been a reported case of eruptive milia in association with nirogacestat therapy. Nirogacestat have been found to induce grade 1 or 2 adverse effects, with exception of hypophosphatemia at grade 3:

Pharmacology

Pharmacodynamics Nirogacestat works as a gamma secretase inhibitor, which blocks the activation of the Notch receptor, stopping tumor growth. Nirogacestat's indirect action on Notch intracellular domain (NICD) and amyloid precursor protein (APP) due to gamma-secretase inhibition are described in the table below.

Nirogacestat's binding to gamma-secretase assessed with cryogenic electron microscopy showed that it localises in the persenilin 1 catalytic subunit. Four hydrogen bonds are involved in this interaction, where two come from lysine (position 380 within the amino-acid sequence of gamma-secretase) and two from leucine (position 432). Its alignment selectively obstructs the site of Notch cleavage by gamma-secretase, which occurs in its β-sheet, allowing inhibition of downstream Notch signalling.

Moreover, nirogacestat's pharmacophore is consistent with other gamma-secretase inhibitors (e.g., crenigacestat) in terms of three dimensional arrangement in the binding cavity. Leucine342 hydrogen bond interaction is shared amongst these compounds A slight modification of nirogacestat's structure, where the propyl group is substituted by a trifluoropropyl group, results in enhanced binding-pocket occupation and better inhibition.

Pharmacokinetics Nirogacestat's pharmacokinetic parameters in patients with desmoid tumors are as follows:

Drug interactions Nirogacestat can interfere with several drugs that are metabolised through cytochrome P450 pathways, especially through CYP3A family and CYP2C19. Additionally, gastric acid-neutralising medications impaired its absorption and thus reduced its plasma concentration.

Chemistry

Physicochemical properties Nirogacestat's chemical properties were evaluated in silico and in vitro in mice and are as follows:

Synthesis Nirogacestat can be synthesised through the following pathway:

2-(2,4-difluorophenyl)acetyl chloride (1) undergoes cyclisation reaction with ethene to yield 2. Then, 2 reacts with tert-butyl (2S)-2-aminopentanoate, yielding 3 that is further hydrolysed to remove the tert-butyl group, yielding 4. To finally obtain nirogacestat, 4 is reacted with 5 ([1-[2-(2,2-dimethylpropylamino)-1,1-dimethyl-ethyl]imidazol-4-yl]azinate). Alternatively, 6 reacts with 7, where the trifluoromethylsulfonate moiety acts as a leaving group and the tert-butyl moiety acts as a protecting group, to avoid the reaction of carboxyl group with amine group in 6. This reaction is performed in iso-propanol and an inorganic acid (such as hydrobromic or hydrochloric acid). Obtained 8 undergoes cyclisation reaction using 9 (1,1'-carbonyldiimidazole) in a polar aprotic solvent, yielding 10. Then, reaction with 11 creates nirogacestat.

The trifluoromethylsulfonyl group in 7 can be replaced with tert-butyloxycarbonyl group (Boc). Reaction of 10 with 11 is conducted a condensing agent, precisely O-(1,2-dihydro-2-oxo-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) in N,N-diisopropylethylamine.

Formation of several side products should be addressed. The above synthetic pathway allows to minimise side product creation to less than 1%. An important example is adverse cyclisation of the product of reaction of 10 with 11 shown below (compound 12). To avoid this situation, to the mixture of 10 and 11, compound 6 and hydrobromic acid is added.Compounds 5 and 11 can be synthesised as follows:

A undergoes reduction using diisobutylaluminium hydride (DIBAL-H) in dichloromethane (DCM), obtaining B. Then B is condensed with 2,2-dimethylpropan-1-amine with Na(OAc)3BH in DCM on a molecular sieve, yielding 5. To synthesise 11, 5 undergoes reduction with hydrogen on Pd/C in methanol. Compound 6 and tert-butyl (2S)-2-aminopentanoate may be synthesised using an enzyme-driven process, using respectively: ATA ω-transaminase with isopropylamine, pyridoxal phosphate, phosphoric acid and potassium hydroxide; alcohol dehydrogenase, glucose dehydrogenase, glucose monohydrate, NAD+ in phosphate buffer and glycerol. This enzymatic process is used to obtain 6 from 2 while minimising stereoisomer side products (the reaction is selective towards the S isomer).

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