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1.
J Med Chem ; 65(24): 16640-16650, 2022 12 22.
Article in English | MEDLINE | ID: mdl-36449304

ABSTRACT

Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the de novo pyrimidine synthesis pathway. Weak inhibitors identified from a high-throughput screening of 240K compounds have been optimized to a potent, orally active agent, compound 27, which has shown significant pharmacological responses at 10 mg/kg dose BID in a well-established animal model of inflammation.


Subject(s)
Carbon-Nitrogen Ligases , Enzyme Inhibitors , Animals , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Carbon-Nitrogen Ligases/metabolism , Cell Proliferation , High-Throughput Screening Assays
2.
Dalton Trans ; 39(30): 7147-52, 2010 Aug 14.
Article in English | MEDLINE | ID: mdl-20601987

ABSTRACT

X-Ray crystal structures, and calculated structures (at B3LYP/6-31G level) are reported for seven N-arylbenzazoles (two carbazoles, indoles and benzimidazoles, and one indazole) bearing electron withdrawing groups in the 2-position of the N-aryl ring. The structures are markedly non-planar by rotation around the N-aryl bond, with the substituent in most cases lying s-E in relation to the N-aryl bond; intermolecular electrostatic interactions in the crystal rationalise the two examples in which an s-Z conformation is observed. A large interplanar angle between the benzazole and the N-aryl planes is associated with a small interplanar angle between the planes of the N-aryl group and the substituent and vice versa.


Subject(s)
Benzimidazoles/chemistry , Indazoles/chemistry , Indoles/chemistry , Computer Simulation , Crystallography, X-Ray , Models, Chemical , Models, Molecular , Molecular Structure
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