Fecha de publicación: -- Fuente: PubMed "hive" Med Chem Res. 2026 Nov 2. doi: 10.1007/s00044-026-03634-2. Online ahead of print.ABSTRACTRemibrutinib (Rhapsido®) is a selective, orally bioavailable covalent inhibitor of Bruton's tyrosine kinase (BTK), approved in 2025 for the treatment of adult chronic spontaneous urticaria (CSU) uncontrolled by H1-antihistamines. By blocking BTK, it suppresses signaling pathways driving mast cell, basophil, and B-cell activation in immune-mediated disease. This review traces remibrutinib's journey from target validation to market approval, detailing the structure-activity relationships that optimized early CGI-560 and CGI-1746 scaffolds into pyrrolopyrimidine and 6-aminopyrimidine series, as well as the process chemistry redesign for commercial synthesis. By covalently capturing BTK in its inactive conformation, remibrutinib achieves exceptional kinase selectivity. This translates into rapid symptom control, convenient oral administration as an alternative to injectable biologics, and a favorable safety profile where mild mucocutaneous bleeding is the primary mechanism-based risk. Remibrutinib is also in late-stage development for other chronic, non-lethal inflammatory conditions including chronic inducible urticaria, hidradenitis suppurativa, Sjögren disease, and multiple sclerosis. Two-panel molecular graphic of the BTK kinase domain in complex with remibrutinib (PDB: 6TFP). The left panel shows a ribbon diagram of the protein. The smaller N-terminal lobe, built around a β-sheet, is coloured yellow. The larger C-terminal lobe, composed mainly of α-helices, is coloured blue. The hinge region, which connects the two lobes, is highlighted in purple. Remibrutinib is drawn as green space-filling spheres, with blue nitrogen, red oxygen and pale cyan fluorine atoms, and sits in the ATP-binding cleft between the two lobes, adjacent to the hinge. The residue Cys481, shown with a gold sulfur atom, lies directly beside the inhibitor, and Tyr551 is labelled on the right.The right panel is an enlarged view of the boxed region, joined to the left panel by red dashed lines. The inhibitor (labelled REMI701) is drawn as green sticks, and the surrounding residues are drawn as thin lines: Leu408, Lys430, Gln412, Tyr551, Met477, Leu528 and Cys481. Dotted lines mark hydrogen bonds between the inhibitor and the backbone of Met477 in the hinge region, the Cys481 residue, and nearby residues such as Gln412.PMID:42970053 | DOI:10.1007/s00044-026-03634-2