title: Discovery of novel BTK inhibitors with carboxylic acids.
abstract: We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: James
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA. Electronic address: jian_liu@merck.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Deodial
authors.initials: D
authors.lastname: Guiadeen
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Arto
authors.initials: A
authors.lastname: Krikorian
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Sobhana Babu
authors.initials: SB
authors.lastname: Boga
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Abdul-Basit
authors.initials: AB
authors.lastname: Alhassan
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Oleg
authors.initials: O
authors.lastname: Selyutin
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Younong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Anand
authors.affiliation: WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Shilan
authors.initials: S
authors.lastname: Liu
authors.affiliation: WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Chundao
authors.initials: C
authors.lastname: Yang
authors.affiliation: WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Maloney
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Ying-Duo
authors.initials: YD
authors.lastname: Gao
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Fischmann
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Presland
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: My
authors.initials: M
authors.lastname: Mansueto
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Zangwei
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Leccese
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang-Hoover
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Knemeyer
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Garlisi
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Bays
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Stivers
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Brandish
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hicks
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Kim
authors.affiliation: Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Joeseph A
authors.initials: JA
authors.lastname: Kozlowski
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002264:Carboxylic Acids / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D002264:Carboxylic Acids; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: Adenosine uptake activity; BTK inhibitor; Carboxylic acid ribose pocket; Off target selectivities; hPBMC and hWB