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Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and In Vitro Metabolic Stability

Popova, Gergana (author)
Karolinska Institutet
Ladds, Marcus J. G. W. (author)
Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17165 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SciLifeLab, SE-17165 Stockholm, Sweden.
Johansson, Lars (author)
Karolinska Inst, Dept Med Biochem & Biophys, SciLifeLab, Chem Biol Consortium Sweden, SE-17121 Stockholm, Sweden.
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Saleh, Aljona (author)
Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab,Drug Discovery & Dev Platform,ADME Therapeut Faci, SE-75123 Uppsala, Sweden.
Larsson, Johanna (author)
Uppsala universitet,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab,Drug Discovery & Dev Platform, SE-75123 Uppsala, Sweden.
Sandberg, Lars (author)
Uppsala universitet,Stockholms universitet,Institutionen för organisk kemi,Science for Life Laboratory (SciLifeLab),Uppsala University, Sweden,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab,Drug Discovery & Dev Platform, SE-75123 Uppsala, Sweden.;Stockholm Univ, Dept Organ Chem, SciLifeLab, Drug Discovery & Dev Platform, SE-17121 Stockholm, Sweden.
Häggblad Sahlberg, Sara (author)
Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Drug Discovery & Dev Platform, SE-17121 Stockholm, Sweden.
Qian, Weixing (author)
Umeå universitet,Kemiska institutionen,Umea Univ, Labs Chem Biol Umea, Chem Biol Consortium Sweden, SE-90187 Umea, Sweden.
Gullberg, Hjalmar (author)
Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Drug Discovery & Dev Platform, SE-17121 Stockholm, Sweden.
Garg, Neeraj (author)
Uppsala universitet,Science for Life Laboratory, SciLifeLab,Kemisk biologi för biomarkörer,Drug Discovery & Dev Platform, SE-75123 Uppsala, Sweden.
Gustavsson, Anna-Lena (author)
Karolinska Institutet
Haraldsson, Martin (author)
Karolinska Institutet
Lane, David (author)
Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17165 Stockholm, Sweden.
Yngve, Ulrika, 1972- (author)
Uppsala universitet,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab,Drug Discovery & Dev Platform, SE-75123 Uppsala, Sweden.
Lain, Sonia (author)
Karolinska Institutet
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Karolinska Institutet Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17165 Stockholm, Sweden;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SciLifeLab, SE-17165 Stockholm, Sweden. (creator_code:org_t)
2020-03-26
2020
English.
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 63:8, s. 3915-3934
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker gamma-H2AX after DHODH inhibition is preventable by cotreatment with the pancaspase inhibitor Z-VAD-FMK. Additional solubility and in vitro m etabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.

Subject headings

NATURVETENSKAP  -- Biologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences (hsv//eng)
NATURVETENSKAP  -- Kemi (hsv//swe)
NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

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