Discovery of Reversible Covalent Bruton's Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib).

Autor:	Owens TD; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Brameld KA; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Verner EJ; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Ton T; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Li X; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Zhu J; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Masjedizadeh MR; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Bradshaw JM; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Hill RJ; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Tam D; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Bisconte A; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Kim EO; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Francesco M; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Xing Y; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Shu J; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Karr D; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., LaStant J; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Finkle D; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Loewenstein N; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Haberstock-Debic H; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Taylor MJ; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Nunn P; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Langrish CL; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States., Goldstein DM; Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Apr 14; Vol. 65 (7), pp. 5300-5316. Date of Electronic Publication: 2022 Mar 18.
DOI:	10.1021/acs.jmedchem.1c01170
Abstrakt:	Bruton's tyrosine kinase (BTK), a Tec family tyrosine kinase, is critical in immune pathways as an essential intracellular signaling element, participating in both adaptive and immune responses. Currently approved BTK inhibitors are irreversible covalent inhibitors and limited to oncology indications. Herein, we describe the design of covalent reversible BTK inhibitors and the discoveries of PRN473 ( 11 ) and rilzabrutinib (PRN1008, 12 ). These compounds have exhibited potent and durable inhibition of BTK, in vivo efficacy in rodent arthritis models, and clinical efficacy in canine pemphigus foliaceus. Compound 11 has completed phase 1 trials as a topical agent, and 12 is in phase 3 trials for pemphigus vulgaris and immune thrombocytopenia.
Databáze:	MEDLINE
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