title: Lead identification of novel and selective TYK2 inhibitors.
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.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Anne
authors.initials: A
authors.lastname: Van Abbema
authors.forename: Liang
authors.initials: L
authors.lastname: Bao
authors.forename: Kathy
authors.initials: K
authors.lastname: Barrett
authors.forename: Maureen
authors.initials: M
authors.lastname: Beresini
authors.forename: Leo
authors.initials: L
authors.lastname: Berezhkovskiy
authors.forename: Wade S
authors.initials: WS
authors.lastname: Blair
authors.forename: Christine
authors.initials: C
authors.lastname: Chang
authors.forename: James
authors.initials: J
authors.lastname: Driscoll
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.forename: Paul
authors.initials: P
authors.lastname: Gibbons
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Pawan Bir
authors.initials: PB
authors.lastname: Kohli
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Lai
authors.forename: Marya
authors.initials: M
authors.lastname: Liimatta
authors.forename: Priscilla
authors.initials: P
authors.lastname: Mantik
authors.forename: Kapil
authors.initials: K
authors.lastname: Menghrajani
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.forename: Amy
authors.initials: A
authors.lastname: Sambrone
authors.forename: Yisong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Steven
authors.initials: S
authors.lastname: Shia
authors.forename: Young
authors.initials: Y
authors.lastname: Shin
authors.forename: Jan
authors.initials: J
authors.lastname: Smith
authors.forename: Sue
authors.initials: S
authors.lastname: Sohn
authors.forename: Mark
authors.initials: M
authors.lastname: Stanley
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Birong
authors.initials: B
authors.lastname: Zhang
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D053634:TYK2 Kinase; C070139:TYK2 protein, human
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