Discovery of (1S,2R,3R)-2,3-Dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: Novel and Highly Selective Aggrecanase Inhibitors
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- 作者：Makoto Shiozaki ; Katsuya Maeda ; Tomoya Miura ; Masayuki Kotoku ; Takayuki Yamasaki ; Isamu Matsuda ; Kenta Aoki ; Katsutaka Yasue ; Hiroto Imai ; Minoru Ubukata ; Akira Suma ; Masahiro Yokota ; Takahiro Hotta ; Masahiro Tanaka ; Yasunori Hase ; Julia Haas ; Andrew M. Fryer ; Ellen R. Laird ; Nicole M. Littmann ; Steven W. Andrews ; John A. Josey ; Takayuki Mimura ; Yuichi Shinozaki ; Hiromi Yoshiuchi ; Takashi Inaba
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：April 28, 2011
- 年：2011
- 卷：54
- 期：8
- 页码：2839-2863
- 全文大小：1576K
- 年卷期：v.54,no.8(April 28, 2011)
- ISSN：1520-4804
文摘
Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1鈥?groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1鈥?groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1鈥?portion of 1,2,3,4-tetrahydropyrido[3鈥?4鈥?4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.