PMID- 28254166
OWN - NLM
STAT- MEDLINE
DCOM- 20170926
LR  - 20181202
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 27
IP  - 6
DP  - 2017 Mar 15
TI  - Discovery of novel BTK inhibitors with carboxylic acids.
PG  - 1471-1477
LID - S0960-894X(16)31244-6 [pii]
LID - 10.1016/j.bmcl.2016.11.079 [doi]
AB  - 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.
CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
FAU - Gao, Xiaolei
AU  - Gao X
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Wang, James
AU  - Wang J
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Liu, Jian
AU  - Liu J
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA. Electronic address: jian_liu@merck.com.
FAU - Guiadeen, Deodial
AU  - Guiadeen D
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Krikorian, Arto
AU  - Krikorian A
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Boga, Sobhana Babu
AU  - Boga SB
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Alhassan, Abdul-Basit
AU  - Alhassan AB
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Selyutin, Oleg
AU  - Selyutin O
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Yu, Wensheng
AU  - Yu W
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Yu, Younong
AU  - Yu Y
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Anand, Rajan
AU  - Anand R
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Liu, Shilan
AU  - Liu S
AD  - WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free 
      Trade Zone, Shanghai 200131, PR China.
FAU - Yang, Chundao
AU  - Yang C
AD  - WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free 
      Trade Zone, Shanghai 200131, PR China.
FAU - Wu, Hao
AU  - Wu H
AD  - WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free 
      Trade Zone, Shanghai 200131, PR China.
FAU - Cai, Jiaqiang
AU  - Cai J
AD  - WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free 
      Trade Zone, Shanghai 200131, PR China.
FAU - Cooper, Alan
AU  - Cooper A
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Zhu, Hugh
AU  - Zhu H
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Maloney, Kevin
AU  - Maloney K
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Gao, Ying-Duo
AU  - Gao YD
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Fischmann, Thierry O
AU  - Fischmann TO
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Presland, Jeremy
AU  - Presland J
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Mansueto, My
AU  - Mansueto M
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Xu, Zangwei
AU  - Xu Z
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Leccese, Erica
AU  - Leccese E
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Zhang-Hoover, Jie
AU  - Zhang-Hoover J
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Knemeyer, Ian
AU  - Knemeyer I
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Garlisi, Charles G
AU  - Garlisi CG
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Bays, Nathan
AU  - Bays N
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Stivers, Peter
AU  - Stivers P
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Brandish, Philip E
AU  - Brandish PE
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Hicks, Alexandra
AU  - Hicks A
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Kim, Ronald
AU  - Kim R
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
FAU - Kozlowski, Joeseph A
AU  - Kozlowski JA
AD  - Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln 
      Avenue, Rahway, NJ 07065, USA.
LA  - eng
PT  - Journal Article
DEP - 20161125
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Carboxylic Acids)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
RN  - EC 2.7.10.2 (BTK protein, human)
SB  - IM
MH  - Agammaglobulinaemia Tyrosine Kinase
MH  - Animals
MH  - Carboxylic Acids/*pharmacology
MH  - *Drug Discovery
MH  - Humans
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors
MH  - Rats
OTO - NOTNLM
OT  - Adenosine uptake activity
OT  - BTK inhibitor
OT  - Carboxylic acid ribose pocket
OT  - Off target selectivities
OT  - hPBMC and hWB
EDAT- 2017/03/04 06:00
MHDA- 2017/09/28 06:00
CRDT- 2017/03/04 06:00
PHST- 2016/11/08 00:00 [received]
PHST- 2016/11/23 00:00 [revised]
PHST- 2016/11/24 00:00 [accepted]
PHST- 2017/03/04 06:00 [pubmed]
PHST- 2017/09/28 06:00 [medline]
PHST- 2017/03/04 06:00 [entrez]
AID - S0960-894X(16)31244-6 [pii]
AID - 10.1016/j.bmcl.2016.11.079 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2017 Mar 15;27(6):1471-1477. doi: 
      10.1016/j.bmcl.2016.11.079. Epub 2016 Nov 25.