This is a stearoyl-CoA desaturase inhibitor. SCD catalyzes the rate-limiting step in the production of monounsaturated fatty acids including oleic and palmitoleic acids from saturated fatty acid precursors. The drug is given orally, and was designed to cross the blood-brain barrier.
Oleic acid and SCD activity were found to promote α-synuclein neurotoxicity, and inhibitors of the enzyme to prevent it (Fanning et al., 2019; Imberdis et al., 2019; Vincent et al., 2018). In a mouse model of Parkinson’s disease, an SCD inhibitor calmed resting tremor and slowed progressive motor decline. Treated mice had less toxic insoluble α-synuclein in their brains, and smaller α-synuclein aggregates in dopaminergic nerve fibers than control mice (Oct 2020 news).
Several companies have identified SCD inhibitors for potential treatment of obesity, diabetes and metabolic disorders, cancer, and acne (Uto, 2016). Adverse events in early phase development included hair loss and dry eye.
As of October 2020, no clinical trials have yet been registered in the U.S. According to a U.S. SEC filing and a company press release, Yumanity has conducted a Phase 1, single-ascending-dose study of YTX-7739 in healthy volunteers. Beginning in October 2019, the study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamic measures, and the effect of food in 56 volunteers who received 5, 10, 30, 100, 250, or 400 mg YTX-7739, given by mouth. The company reported no serious or unexpected adverse events. The most frequent adverse event was headache. Pharmacokinetics were dose proportional from 5 to 250 mg when the drug was given with food.
The company is planning a multiple dosing safety study in healthy volunteers, and a Phase 1b safety and biomarker study in people with Parkinson’s disease.
Last Updated: 23 Oct 2020
- Fanning S, Haque A, Imberdis T, Baru V, Barrasa MI, Nuber S, Termine D, Ramalingam N, Ho GP, Noble T, Sandoe J, Lou Y, Landgraf D, Freyzon Y, Newby G, Soldner F, Terry-Kantor E, Kim TE, Hofbauer HF, Becuwe M, Jaenisch R, Pincus D, Clish CB, Walther TC, Farese RV Jr, Srinivasan S, Welte MA, Kohlwein SD, Dettmer U, Lindquist S, Selkoe D. Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Mol Cell. 2019 Mar 7;73(5):1001-1014.e8. Epub 2018 Dec 4 PubMed.
- Vincent BM, Tardiff DF, Piotrowski JS, Aron R, Lucas MC, Chung CY, Bacherman H, Chen Y, Pires M, Subramaniam R, Doshi DB, Sadlish H, Raja WK, Solís EJ, Khurana V, Le Bourdonnec B, Scannevin RH, Rhodes KJ. Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity. Cell Rep. 2018 Dec 4;25(10):2742-2754.e31. PubMed.
- Uto Y. Recent progress in the discovery and development of stearoyl CoA desaturase inhibitors. Chem Phys Lipids. 2016 May;197:3-12. Epub 2015 Sep 3 PubMed.
- Atkinson KA, Beretta EE, Brown JA, Castrodad M, Chen Y, Cosgrove JM, Du P, Litchfield J, Makowski M, Martin K, McLellan TJ, Neagu C, Perry DA, Piotrowski DW, Steppan CM, Trilles R. N-benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1621-5. Epub 2011 Jan 31 PubMed.
- Terry-Kantor E, Tripathi A, Imberdis T, LaVoie ZM, Ho GP, Selkoe D, Fanning S, Ramalingam N, Dettmer U. Rapid Alpha-Synuclein Toxicity in a Neural Cell Model and Its Rescue by a Stearoyl-CoA Desaturase Inhibitor. Int J Mol Sci. 2020 Jul 22;21(15) PubMed.
- Imberdis T, Negri J, Ramalingam N, Terry-Kantor E, Ho GP, Fanning S, Stirtz G, Kim TE, Levy OA, Young-Pearse TL, Selkoe D, Dettmer U. Cell models of lipid-rich α-synuclein aggregation validate known modifiers of α-synuclein biology and identify stearoyl-CoA desaturase. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20760-20769. Epub 2019 Sep 23 PubMed.
- Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Scherzer CR, Hauser MA, Scott WK, Small GW, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Mastaglia F, Middleton LT, Roses AD, Saunders AM, Schmechel DE, Gullans SR, Haines JL, Gilbert JR, Vance JM, Pericak-Vance MA, Hulette C, Welsh-Bohmer KA. Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet. 2003 Dec 15;12(24):3259-67. PubMed.
- Niida Y, Masuda M, Adachi Y, Yoshizawa A, Ohminami H, Mori Y, Ohnishi K, Yamanaka-Okumura H, Uchida T, Nikawa T, Yamamoto H, Miyazaki M, Taketani Y. Reduction of stearoyl-CoA desaturase (SCD) contributes muscle atrophy through the excess endoplasmic reticulum stress in chronic kidney disease. J Clin Biochem Nutr. 2020 Sep;67(2):179-187. Epub 2020 Jun 9 PubMed.