title: Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies.
abstract: Starting with a lead [1,5-a]pyrimidin-7(4H)-one-containing molecule (1), we generated potent, selective and orally bioavailable KDM5 inhibitors. Using structure- and property-based approaches, we designed 48 with improved cell potency (PC9 H3K4Me3 EC50=0.34μM). Furthermore, 48 maintained suitable physiochemical properties and displayed an excellent pharmacokinetic (PK) profile in mice. When dosed orally in mice at 50mg/kg twice a day (BID), 48 showed an unbound maximal plasma concentration (Cmax) >15-fold over its cell EC50, thereby providing a robust chemical probe for studying KDM5 biological functions in vivo.
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: liang.jun@gene.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Birong
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sharada
authors.initials: S
authors.lastname: Labadie
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Maia
authors.initials: M
authors.lastname: Vinogradova
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Kiefer
authors.affiliation: Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Gehling
authors.affiliation: Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.affiliation: Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Cummings
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Tommy
authors.initials: T
authors.lastname: Lai
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Jiangpeng
authors.initials: J
authors.lastname: Liao
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Gustafson
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Van der Porten
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Mao
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Classon
authors.affiliation: Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trojer
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Lesley
authors.initials: L
authors.lastname: Murray
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005260:Female; D006207:Half-Life; D006657:Histones / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D056485:Retinoblastoma-Binding Protein 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006657:Histones; D011720:Pyrazoles; D011744:Pyrimidinones; C000621409:pyrazolo(1,5-a)pyrimidin-7(4H)-one; C577458:KDM5A protein, mouse; D056485:Retinoblastoma-Binding Protein 2
keywords: Drug resistance; Epigenetics; Histone demethylase; KDM5; Lead optimization; Selective KDM5 inhibitors