Wang, Bing Chu, Daniel Feng, Ying Shen, Yuqiao Aoyagi-Scharber, Mika Post, Leonard E. Discovery and Characterization of (8<i>S</i>,9<i>R</i>)‑5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl‑1<i>H</i>‑1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro‑3<i>H</i>‑pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent We discovered and developed a novel series of tetrahydro­pyrido­phthlazinones as poly­(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8<i>S</i>,9<i>R</i>)-<b>47</b> (talazoparib; BMN 673; (8<i>S</i>,9<i>R</i>)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1<i>H</i>-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3<i>H</i>-pyrido­[4,3,2-de]­phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8<i>S</i>,9<i>R</i>)-<b>47</b> demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with <i>K</i><sub>i</sub> = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC<sub>50</sub> of 2.51 nM and prevents proliferation of cancer cells carrying mutant <i>BRCA1</i>/<i>2</i>, with EC<sub>50</sub> = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8<i>S</i>,9<i>R</i>)-<b>47</b> is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the <i>BRCA1</i> mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8<i>S</i>,9<i>R</i>)-<b>47</b> has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline <i>BRCA1</i>/<i>2</i> deleterious mutations. BRCA;BMN;PK;PARP 2 enzyme activity;MX;EC 50;nM;phase;breast cancer xenograft model 2016-01-14
    https://acs.figshare.com/articles/journal_contribution/Discovery_and_Characterization_of_8_i_S_i_9_i_R_i_5_Fluoro_8_4_fluorophenyl_9_1_methyl_1_i_H_i_1_2_4_triazol_5_yl_2_7_8_9_tetrahydro_3_i_H_i_pyrido_4_3_2_de_phthalazin_3_one_BMN_673_Talazoparib_a_Novel_Highly_Potent_and_Orally_Efficacious_Poly_ADP_ribose_/2563090
10.1021/acs.jmedchem.5b01498.s001