SAR studies toward discovery of emvododstat (PTC299), a potent dihydroorotate dehydrogenase (DHODH) inhibitor.

Autor: Baiazitov RY; PTC USA, NJ Center of Excellence Campus, 1013 Route 202/206, Bridgewater, NJ, 08807, USA. Electronic address: rbaiazitov@ptcbio.com., Qi H, Arasu T; Lachman Consultant Services, Inc., 1600 Stewart Ave, Suite 604, Westbury, NY, 11590, USA., Lennox W; PTC USA, Hopewell, 311 Pennington Rocky Hill Rd., Pennington, NJ, 08534, USA., Cao L; PTC USA, NJ Center of Excellence Campus, 1013 Route 202/206, Bridgewater, NJ, 08807, USA., Weetall M; PTC USA, NJ Center of Excellence Campus, 1013 Route 202/206, Bridgewater, NJ, 08807, USA., Furia B; PTC Therapeutics Inc, 100 Corporate Ct, South Plainfield, NJ, 07080, USA., Zhuo J; PTC Therapeutics Inc, 100 Corporate Ct, South Plainfield, NJ, 07080, USA., Choi S; Avelos Therapeutics, Inc., 21 Magokjungang 8-ro 7-gil, Gangseo-gu, Seoul, 07794, Republic of Korea., Kim MJ; PTC USA, NJ Center of Excellence Campus, 1013 Route 202/206, Bridgewater, NJ, 08807, USA., Sheedy J; PTC USA, NJ Center of Excellence Campus, 1013 Route 202/206, Bridgewater, NJ, 08807, USA., Davis T; Recludix Pharmaceuticals, 3545 John Hopkins Blvd, Suite 150, San Diego, CA, 92121, USA., Moon YC; PTC USA, NJ Center of Excellence Campus, 1013 Route 202/206, Bridgewater, NJ, 08807, USA.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Dec 15; Vol. 244, pp. 114826. Date of Electronic Publication: 2022 Oct 05.
DOI: 10.1016/j.ejmech.2022.114826
Abstrakt: Dihydroorotate dehydrogenase (DHODH) is the enzyme that catalyzes a rate-determining step during the de novo synthesis of uridine, an important source of cellular pyrimidine nucleotides. Ability to modulate the activity of this enzyme may be used to control diseases associated with rapid, out-of-control cell growth in oncology, immunology, and virology. Emvododstat (PTC299) is a tetrahydro-β-carboline DHODH inhibitor discovered through the GEMS technology (Gene Expression Modulation by Small-Molecules). Described in this paper is the lead optimization campaign that culminated in the discovery of this highly potent DHODH inhibitor.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ramil Y. Baiazitov, Hongyan Qi, Tamil Arasu, William Lennox, Liangxian Cao, Marla Weetall, Bansri Furia, Jin Zhuo, Soongyu Choi, Min Jung Kim, Josephine Sheedy, Thomas Davis, Young-Choon Moon reports financial support was provided by PTC Therapeutics Inc. Hongyan Qi, Tamil Arasu, William Lennox, Liangxian Cao, Soongyu Choi, Min Jung Kim, Thomas Davis, Young-Choon Moon has patent issued to PTC Therapeutics.
(Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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