|5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-酰胺|CsnPharm

CAS No.: 2589531-76-8

Saruparib Catalog No. CSN32732

Synonyms: AZD5305

AZD-5305 is a potent and highly selective PARP1 inhibitor. AZD5305 dosed at 0.1mg/kg QD or higher for 35 days delivered about 90% regression in the BRCA1m triple-negative breast cancer (TNBC) xenograft model MDA-MB-436.

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技术信息

生物活性

描述Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins. PARPs play an important role in various cellular processes, including modulation of chromatin structure, transcription, replication, recombination, and DNA repair Julio Morales, Longshan Li,et al.| Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr. 2014;24(1):15-28.| https://pubmed.ncbi.nlm.nih.gov/24579667/. AZD5305 is a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. It is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro. AZD5305 combines excellent potency to PARP1 with superior selectivity toward PARP2, reaching almost 10,000-fold. AZD5305 exhibited very low plasma clearances (CLp) of 0.23, 1.1, 0.33, and 0.84 mL/min/kg and generally low steady-state volumes of distribution (Vss) of 0.17,0.38, 0.30, and 0.38 L/kg in the mouse, rat, dog, and monkey, respectively. The resulting plasma half-lives were 8.0, 4.6, 10,and 7.1 h, respectively. The oral bioavailability of AZD5305 was high across all species, consistent with the low hepatic clearance and a high fraction absorbed. The unbound clearance of ≤34 mL/min/kg, in combination with high potency, was expected to drive low efficacious doses in vivo which was predicted to carry through to humans based on the equally low in vitro CLint values^[1].
参考文献

[1] Jeffrey W Johannes, Amber Balazs,et al. Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs. J Med Chem. 2021 Oct 14;64(19):14498-14512.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.4601 mL
- 12.3007 mL
- 24.6014 mL
- 5 mM
- 0.4920 mL
- 2.4601 mL
- 4.9203 mL
- 10 mM
- 0.2460 mL
- 1.2301 mL
- 2.4601 mL

技术信息

CAS号	2589531-76-8	储存条件	粉末 Inert atmosphere,Room Temperature 液体 -20°C:3-6 月 -80°C:12月
分子式	C22H26N6O2	运输	蓝冰
分子量	406.48	别名	AZD5305

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