Open AccessPyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties
Author(s) -
Ganesha Rai,
Daniel J. Urban,
Bryan T. Mott,
Xin Hu,
ShyhMing Yang,
Gloria A. Benavides,
Michelle S. Johnson,
G Squadrito,
Kyle R. Brimacombe,
Tobie D. Lee,
Dorian M. Cheff,
Hongguang Zhu,
Mark J. Henderson,
Katherine Pohida,
Gary A. Sulikowski,
David M. Dranow,
M. D. Kabir,
Pranav Shah,
Elias Carvalho Padilha,
Dingyin Tao,
Yuhong Fang,
Plamen P. Christov,
KwangHo Kim,
Somnath Jana,
Pavan Muttil,
Tamara L. Anderson,
Nitesh K. Kunda,
Helen J. Hathaway,
Donna F. Kusewitt,
Nobu Oshima,
Murali Krishna Cherukuri,
D.R. Davies,
Jeffrey P. Norenberg,
Larry A. Sklar,
William Moore,
Chi V. Dang,
Gordon M. Stott,
Leonard Μ. Neckers,
Andrew Flint,
Victor DarleyUsmar,
Anton Simeonov,
Alex G. Waterson,
Ajit Jadhav,
Matthew D. Hall,
David J. Maloney
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00916
Subject(s) - in vivo , chemistry , lactate dehydrogenase , glycolysis , nicotinamide adenine dinucleotide , pyrazole , lactate dehydrogenase a , pharmacology , biochemistry , nad+ kinase , potency , in vitro , enzyme , stereochemistry , biology , microbiology and biotechnology
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo , possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug-target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo . The lead compounds, named NCATS-SM1440 ( 43 ) and NCATS-SM1441 ( 52 ), possess desirable attributes for further studying the effect of in vivo LDH inhibition.