4gmy

Publication Abstract from PubMed

A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.

Lead identification of novel and selective TYK2 inhibitors.,Liang J, Tsui V, Van Abbema A, Bao L, Barrett K, Beresini M, Berezhkovskiy L, Blair WS, Chang C, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liimatta M, Mantik P, Menghrajani K, Murray J, Sambrone A, Xiao Y, Shia S, Shin Y, Smith J, Sohn S, Stanley M, Ultsch M, Zhang B, Wu LC, Magnuson S Eur J Med Chem. 2013 May 14;67C:175-187. doi: 10.1016/j.ejmech.2013.03.070. PMID:23867602^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.