Synthesis and Evaluation of Structurally Diverse C-2-Substituted Thienopyrimidine-Based Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase

Abstract

Novel analogues of C-2-substituted thienopyrimidine-based bisphosphonates (C2-ThP-BPs) are described that are potent inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS). Members of this class of compounds induce target-selective apoptosis of multiple myeloma (MM) cells and exhibit antimyeloma activity in vivo. A key structural element of these inhibitors is a linker moiety that connects their (((2-phenylthieno­[2,3-d]­pyrimidin-4-yl)­amino)­methylene)­bisphosphonic acid core to various side chains. The structural diversity of this linker moiety, as well as the side chains attached to it, was investigated and found to significantly impact the toxicity of these compounds in MM cells. The most potent inhibitor identified was evaluated in mouse and rat for liver toxicity and systemic exposure, respectively, providing further optimism for the potential value of such compounds as human therapeutics.

Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

“…In 2022, Lee et al. conducted further studies with the same Th‐BP GGSI 186 . Here, they reported that seven days after administration of a single dose of GGSI (up to 10 mg/kg via IV administration), no abnormalities in liver function tests were observed.…”

“…The extension of the thienopyrimidine moiety was shown to increase potency due to its extension into the IPP binding site. However, this was only seen in compounds with a modification at the C‐2 position, while modification at the C‐6 position was found to increase potency for inhibition of FDPS instead 185,186 …”

“…However, this was only seen in compounds with a modification at the C‐2 position, while modification at the C‐6 position was found to increase potency for inhibition of FDPS instead. 185 , 186 …”

Discovery and Evaluation of C6-Substituted Pyrazolopyrimidine-Based Bisphosphonate Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase and Evaluation of Their Antitumor Efficacy in Multiple Myeloma, Pancreatic Ductal Adenocarcinoma, and Colorectal Cancer

“…During our initial investigations into selective hGGPPS inhibitors, we reported the synthesis and biological evaluation of hGGPPS inhibitors 11 and 12 (Figure ), having a 2-phenylthieno­[2,3- d ]­pyrimidin-4-amine core structure . Several other analogs with various scaffold modifications were also explored and found to inhibit the human GGPPS and block cancer cell proliferation .…”

“…For a more modular approach (amenable to parallel library synthesis), we decided to first protect the N1 of the pyrazolopyrimidine with a tetrahydropyranyl (THP) group, following a previously reported protocol . Subsequently, S N Ar displacement of the C-4 chloro with ammonia gave 6-chloro-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo­[3,4- d ]­pyrimidin-4-amine, which upon treatment with diethyl phosphite and triethyl orthoformate gave compound 22 , as we previously reported . Removal of the THP group under acidic conditions gave intermediate 23 , which was used as the precursor to the N1- and N2-alkylated intermediates 24a – c and 25a , b , respectively (Scheme ).…”