Pamiparib

Pamiparib (BGB-290) is an investigational small molecule inhibitor of PARP1 and PARP2. Pamiparib is being evaluated as a monotherapy in pivotal clinical trials in China in recurrent platinum-sensitive and BRCA1/2 mutated ovarian cancers.

Pamiparib, is a PARP inhibitor, which can be used as an anticancer agent.

Pamiparib inhibits the activity of PARP enzymes, interfering with the DNA damage repair mechanism of tumor cells, especially in those cancer cells with BRCA gene mutations, which have become dependent on the PARP-mediated repair pathway to maintain the stability of their genome. Therefore, pamiparib can increase DNA damage in these tumor cells, leading to tumor cell death.

Using 2-bromo-5-fluorobenzoic acid (27.1) as the raw material, a series of reactions were performed to obtain methyl benzoate 27.2, which was then reduced and protected to obtain the key aromatic bromide fragment 27.3. Using pyrrolene 27.4 as the raw material, alkane 27.8 was obtained by reaction with tert-butyl bromoacetate 27.5, addition of acetylene group, removal of silicon group, etc., and then enantiomer separation was performed to obtain the desired (R)-enantiomer 27.10. The alkynyl group 27.10 and the bromide group 27.3 were subjected to Larock heterocyclization reaction to generate indole 27.11, which was then treated with trifluoromethanesulfonic acid and hydrazine hydrate reaction to finally obtain Pamiparib (27) as a semihydrate crystalline solid with a yield of 50%.

Oral administration of Pamiparib results in time-dependent and dose-dependent inhibition of PARylation in MDA-MB-436 (BRCA1 mutant) breast cancer xenograft, correlating well with the tumor drug concentrations. It has also demonstrated good combination activity with chemotherapeutics in patient biopsy derived SCLC models. Also Pamiparib has significant brain penetration in C57 mice. The drug exposure in brain vs. that in plasma was close to 20% after oral administration of BGB-290.

PARP