Category: 1297537-37-1

Taavitsainen, Paivi published the artcileMetabolism and mass balance of the novel nonsteroidal androgen receptor inhibitor darolutamide in humans, Computed Properties of 1297537-37-1, the publication is Drug Metabolism & Disposition (2021), 49(6), 420-433, database is CAplus and MEDLINE.

The biotransformation and excretion of darolutamide were investigated in a phase I study. Six healthy male volunteers received a single dose of 300 mg ¹⁴C-darolutamide as an oral solution in the fasted state. Plasma, urine, and feces samples were analyzed for mass balance evaluation by liquid scintillation counting (LSC). Metabolite profiling and identification were determined using liquid chromatog. mass-spectrometry with off-line radioactivity detection using LSC. Complete mass balance was achieved, with mean radioactivity recovery of 95.9% within 168 h (63.4% in urine, 32.4% in feces). The administered 1:1 ratio of (S,R)- and (S,S)-darolutamide changed to approx. 1:5, resp., in plasma. Darolutamide and the oxidation product, keto-darolutamide, were the only components quantifiable by LSC in plasma, accounting for 87.4% of total radioactivity, with a 2.1-fold higher plasma exposure for keto-darolutamide. Aside from darolutamide, the most prominent metabolites in urine were O-glucoronide (M-7a/b) and N-glucuronide (M-15a/b), as well as pyrazole sulfates (M-29, M-24) and glucuronides (M-21, M-22) resulting from oxidative cleavage of the parent. The darolutamide diastereomers were mainly detected in feces. In vitro assays showed that darolutamide metabolism involves a complex interplay between oxidation and reduction, as well as glucuronidation. Interconversion of the diastereomers involves oxidation to keto-darolutamide, primarily mediated by CYP3A4, followed by reduction predominantly catalyzed by cytosolic reductase(s), with aldo-keto reductase 1C3 playing the major role. The latter reaction showed stereoselectivity with preferential formation of (S,S)-darolutamide.

Drug Metabolism & Disposition published new progress about 1297537-37-1. 1297537-37-1 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Chloride,Nitrile,Benzene, name is 2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile, and the molecular formula is C17H20ClN3, Computed Properties of 1297537-37-1.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Yu, Jiang published the artcileDiscovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants, Product Details of C10H6ClN3, the publication is European Journal of Medicinal Chemistry (2019), 111608, database is CAplus and MEDLINE.

Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, down-regulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also down-regulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-pos. 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clin. used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and down-regulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.

European Journal of Medicinal Chemistry published new progress about 1297537-37-1. 1297537-37-1 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Chloride,Nitrile,Benzene, name is 2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile, and the molecular formula is C14H20BNO3, Product Details of C10H6ClN3.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics