Liang, Jun published the artcileFrom a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors, Related Products of pyrazoles-derivatives, the publication is Bioorganic & Medicinal Chemistry Letters (2017), 27(13), 2974-2981, database is CAplus and MEDLINE.
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog, [3-(4-bromo-1H-pyrazol-1-yl)-1-pyrrolidinyl][5-(1-methylethyl)-1H-pyrazol-3-yl]methanone (35), of which the authors obtained a co-crystal structure with KDM5A. Using structure-based design approach, the authors identified, N-[(3R)-1-[[5-(1-methylethyl)-1H-pyrazol-3-yl]carbonyl]-3-pyrrolidinyl]cyclopropanecarboxamide (50), with improved biochem., cell potency and reduced MW and lower lipophilicity (Log D) compared with the original hit. Furthermore, 50 showed lower clearance than [5-(1-methylethyl)-1H-pyrazol-3-yl][(3S)-3-[6-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-pyridinyl]-1-pyrrolidinyl]methanone (9) in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5 mg/kg resulted in unbound Cmax ∼2-fold of its cell potency (PC9 H3K4Me3 0.96 μM), meeting the authors’ criteria for an in vivo tool compound from a new scaffold.
Bioorganic & Medicinal Chemistry Letters published new progress about 890590-91-7. 890590-91-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Carboxylic acid, name is 3-Isopropyl-1H-pyrazole-5-carboxylic acid, and the molecular formula is C7H10N2O2, Related Products of pyrazoles-derivatives.
Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics