2. Academic Validation
  3. Lead identification of novel and selective TYK2 inhibitors

Lead identification of novel and selective TYK2 inhibitors

  • Eur J Med Chem. 2013 Sep:67:175-87. doi: 10.1016/j.ejmech.2013.03.070.
Jun Liang 1,  Vickie Tsui,  Anne Van Abbema,  Liang Bao,  Kathy Barrett,  Maureen Beresini,  Leo Berezhkovskiy,  Wade S Blair,  Christine Chang,  James Driscoll,  Charles Eigenbrot,  Nico Ghilardi,  Paul Gibbons,  Jason Halladay,  Adam Johnson,  Pawan Bir Kohli,  Yingjie Lai,  Marya Liimatta,  Priscilla Mantik,  Kapil Menghrajani,  Jeremy Murray,  Amy Sambrone,  Yisong Xiao,  Steven Shia,  Young Shin,  Jan Smith,  Sue Sohn,  Mark Stanley,  Mark Ultsch,  Birong Zhang,  Lawren C Wu,  Steven Magnuson
Affiliations

Affiliation

  • 1 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
PMID: 23867602 DOI: 10.1016/j.ejmech.2013.03.070
Abstract

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.

Keywords

1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; 4-(N,N-dimethylamino)pyridine; ADME; AcOH; Boc; CDCl(3); Crystal structure; DCE; DCM; DMAP; DMF; DMSO; DMSO-d(6); DTT; EDCI; ESI; HATU; HOBt; Hit to lead; IV; Immunology; Janus family kinase; Kinase inhibitor; LCMS; LogD(7.4); MCT; MDCK; Madin–Darby canine kidney cells; P(app); PO; Ph; SCX-2; SFC; Structure–activity relationship; TCEP; TFA; THF; TLC; TYK2BME; Tf; absorption, distribution, metabolism, and excretion; acetic acid; apparent permeability; aq.; aqueous; by mouth; deuterated DMSO; deuterated chloroform; dichloroethane; dichloromethane; dimethylformamide; dimethylsulfoxide; dithiothreitol; electrospray ionization; h; hour; hydroxybenzotriazole; intravenous; liquid chromatography–mass spectrometry; log of partition coefficient between octanol and pH(7.4) aqueous buffer; methyl cellulose/tween; p-TsOH; para-toluenesulfonic acid; phenyl; pre-packed Isolute(®) silica-based sorbent with a chemically bonded propylsulfonic acid functional group; supercritical fluid chromatography; tert-butyl carbamate; tetrahydrofuran; thin layer chromatography; trifluoroacetic acid; trifluorosulfonate; tris(2-carboxyethyl)phosphine; β-mercaptoethanol.

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