Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors

Abstract

Macrocyclization has been frequently utilized for optimizing peptide or peptidomimetic-based compounds. In an attempt to obtain potent, metabolically stable, and orally available proteasome inhibitors, 30 oprozomib-derived macrocyclic peptides with structural diversity in their N-terminus and linker were successively designed and synthesized for structure− activity relationship (SAR) studies. As a consequence, the macrocyclic peptides with N-methyl-pyrazole (24p, 24x), imidazole (24t), and pyrazole (24v) as their respective N-termini exhibited favorable in vitro activity and metabolic stability, which translated into their potent in vivo proteasome inhibitory activity after oral administration. In particular, compound 24v, as the most distinguished one among this series, displayed excellent chymotrypsin-like (ChT-L, β5) inhibitory potency (IC 50 = 16 nM), low nanomolar antiproliferative activity against all three of the tested cell lines, and superior metabolic stability in mouse liver microsome (MLM), as well as favorable inhibition against ChT-L compared to that of oprozomib in BABL/c mice following po administration at a comparatively low dose, thereby representing a promising candidate for further development.

Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer’s Disease

“…These macrocyclic peptide epoxyketones are highly selective to iP, unlike the previously reported macrocyclic analogues of the anti-cancer agent oprozomib, which targets both cP and iP. 44 Besides, these compounds are structurally unique, having a proline or proline mimic at the P3 position as a handle for P2−P3 or P2− P4 macrocyclization. In particular, our lead macrocyclic iP inhibitor, DB-60 (20), showed significantly improved metabolic stability and decreased interaction with the two major drug transporters in the BBB, ABCB1 and ABCG2.…”

“…To this end, we were able to synthesize 17 macrocyclic peptides retaining the epoxyketone pharmacophore. These macrocyclic peptide epoxyketones are highly selective to iP, unlike the previously reported macrocyclic analogues of the anti-cancer agent oprozomib, which targets both cP and iP . Besides, these compounds are structurally unique, having a proline or proline mimic at the P3 position as a handle for P2–P3 or P2–P4 macrocyclization.…”

Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit

“…Despite covalent-reversible inhibitors of the proteasome representing the first class of proteasome inhibitors, e. g. peptidic boronic acids and aldehydes, the drug development of reversible binding warheads has remained underexplored over the last decade, focusing instead on irreversible acting warheads such as epoxyketones and sulfonyl fluorides. [37][38][39] Furthermore, explorations of structure-activity relationships of inhibitors targeting the primed site of β5 have been reported only occasionally. Our group previously reported the identification of ketoamide 7 that displays increased inhibitory activity compared to unsubstituted phenyl ketoamide 6 and allows for subsequent modification occupying the S1' pocket.…”

Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design

“…Conformational restriction is one of the most effective methodologies for drug design, since it can help improve the PK profiles of compounds and stabilize a favorable binding pattern to improve the binding affinities or kinase isoform selectivity. , This strategy has been widely applied in drug discovery. , In fact, some Food and Drug Administration-approved drugs were discovered and developed by using conformational restriction, such as Dolutegravir . In our previous study, the discovery of a series of 4,4-disubstituted piperidine derivatives featuring more restricted conformations in contrast to GSK-795 were successfully achieved, − which proved that conformational restriction strategy could be used for discovery of new Akt inhibitors with novel skeletons.…”

“…21,22 This strategy has been widely applied in drug discovery. 22,23 In fact, some Food and Drug Administrationapproved drugs were discovered and developed by using conformational restriction, such as Dolutegravir. 24 In our previous study, the discovery of a series of 4,4-disubstituted piperidine derivatives featuring more restricted conformations in contrast to GSK-795 were successfully achieved, 25−29 which proved that conformational restriction strategy could be used for discovery of new Akt inhibitors with novel skeletons.…”