Design and Synthesis of an Orally Bioavailable and Selective Peptide Epoxyketone Proteasome Inhibitor (PR-047)

• Published in: Journal of medicinal chemistry 2009-05, Vol.52 (9), p.3028-3038
• Main Authors: Zhou, Han-Jie, Aujay, Monette A, Bennett, Mark K, Dajee, Maya, Demo, Susan D, Fang, Ying, Ho, Mark N, Jiang, Jing, Kirk, Christopher J, Laidig, Guy J, Lewis, Evan R, Lu, Yan, Muchamuel, Tony, Parlati, Francesco, Ring, Eileen, Shenk, Kevin D, Shields, Jamie, Shwonek, Peter J, Stanton, Timothy, Sun, Congcong M, Sylvain, Catherine, Woo, Tina M, Yang, Jinfu
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biological Availability; Cell Line; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacokinetics; Dipeptides - pharmacology; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; General aspects; Humans; Kinetics; Medical sciences; Mice; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacokinetics; Oligopeptides - pharmacology; Pharmacology. Drug treatments; Proteasome Inhibitors; Structure-Activity Relationship; Substrate Specificity; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacokinetics; Thiazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801329v

Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and Non-Hodgkin’s lymphoma. Carfilzomib, an epoxyketone currently undergoing clinical trials in malignant diseases, is a highly selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. A chemistry effort was initiated to discover orally bioavailable analogues of carfilzomib, which would have potential for improved dosing flexibility and patient convenience over intravenously administered agents. The lead compound, 2-Me-5-thiazole-Ser(OMe)-Ser(OMe)-Phe-ketoepoxide (58) (PR-047), selectively inhibited CT-L activity of both the constitutive proteasome (β5) and immunoproteasome (LMP7) and demonstrated an absolute bioavailability of up to 39% in rodents and dogs. It was well tolerated with repeated oral administration at doses resulting in >80% proteasome inhibition in most tissues and elicited an antitumor response equivalent to intravenously administered carfilzomib in multiple human tumor xenograft and mouse syngeneic models. The favorable pharmacologic profile supports its further development for the treatment of malignant diseases.