Author: Kojima, Naoki ; Nishimoto, Tomohiro ; Takeda, Takuya ; Hitaka, Kosuke ; Ohara, Hiroki ; Tabuse, Hideaki ; Oka, Yusuke ; Yahara, Tohru ; Ochiai, Nagahiro ; Fukunaga, Takuya ; Gunji, Emi ; Asami, Taiji ; Abe-Sato, Kumi ; Kamitani, Masafumi ; Yasukawa, Yoshifumi ; Kumasaka-Abe, Tomoko

Matrix metalloproteinase-7 (MMP-7) has been shown to play an important role in pathophysiological processes such as cancer and fibrosis. We previously discovered selective MMP-7 inhibitors by molecular hybridization and structure-based drug design. However, the systemic clearance (CL_tot) of the biologically active lead compound was very high. Because our studies revealed that hepatic uptake by organic anion transporting polypeptide (OATP) was responsible for the high CL_tot, we found a novel approach to reducing their uptake based on isoelectric point (IP) values as an indicator for substrate recognition by OATP1B1/1B3. Our "IP shift strategy" to adjust the IP values culminated in the discovery of TP0628103 (18), which is characterized by reduced in vitro OATP-mediated hepatic uptake and in vivo CL_tot. Our in vitro-in vivo extrapolation of OATP-mediated clearance and the "IP shift strategy" provide crucial insights for a new medicinal chemistry approach to reducing the systemic clearance of OATP1B1/1B3 substrates.

09 Nov 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Structure-Based Optimization and Biological Evaluation of Potent and Selective MMP-7 Inhibitors for Kidney Fibrosis

Q1 · MEDICINE

Article

Author: Oka, Yusuke ; Kanazawa, Harumi ; Gunji, Emi ; Abe-Sato, Kumi ; Tokura, Seiken ; Yahara, Tohru ; Endo, Mayumi ; Takeda, Takuya ; Kojima, Naoki ; Hitaka, Kosuke ; Tabuse, Hideaki ; Kamitani, Masafumi ; Wakabayashi, Satoshi

Matrix metalloproteinase-7 (MMP-7) has been shown to play important roles in pathophysiological processes involved in the development/progression of diseases such as cancer and fibrosis. We discovered selective MMP-7 inhibitors composed of arylsulfonamide, carboxylate, and short peptides by a molecular hybridization approach. These compounds interacted with MMP-7 via multiple hydrogen bonds in the cocrystal structures. To obtain compounds for in vivo evaluation, we attempted structural optimization, particularly targeting Tyr167 at the S3 subsite through structure-based drug design, and identified compound 15 as showing improved MMP-7 potency and MMP subtype selectivity. A novel π-π stacking interaction with Tyr167 was achieved when 4-pyridylalanine was introduced as the P3 residue. Compound 15 suppressed the progression of kidney fibrosis in a dose-dependent manner in a mouse model of unilateral ureteral obstruction. Thus, we demonstrated, for the first time, that potent and selective MMP-7 inhibitors could prevent the progression of kidney fibrosis.

13 Oct 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Highly Potent and Selective Matrix Metalloproteinase-7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides

Q1 · MEDICINE

Article

Author: Tabuse, Hideaki ; Kanazawa, Harumi ; Kamitani, Masafumi ; Mitani, Akiko ; Abe-Sato, Kumi ; Kojima, Naoki ; Oka, Yusuke ; Gunji, Emi ; Hitaka, Kosuke ; Yashiro, Miyoko ; Tamura, Yunoshin

Matrix metalloproteinase-7 (MMP-7) has emerged as a protein playing important roles in both physiological and pathophysiological processes. Despite the growing interest in MMP-7 as a potential therapeutic target for diseases including cancer and fibrosis, potent and selective MMP-7 inhibitors have yet to be identified. Compound 1, previously reported by Edman and co-workers, binds to the S1' subsite of MMP-7, exhibiting moderate inhibitory activity and selectivity. To achieve both higher inhibitory activity and selectivity, we conceived hybridizing 1 with short peptides. The initially designed compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over other MMP subtypes.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Preclinical	CN	Brilliant Pharmaceutical Co. Ltd.	-

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