[PROC. AMER. ASSOC. CANCER RES. 40, March 1999]
Copyright © 1999 by the American Association for Cancer Research
#3433 Development of a novel, highly-selective, potent MMP inhibitor, AG3433, with high oral
bioavailability and antitumor activity. Shalinsky, D.R.1,6, Koudriakova, T.2, McDermott, C.1, Zhu, J.2, Zou, H.1,6,
Brekken, J.1,6, Deal, J.3, Margosiak, S.4, McTigue, M.5, Wickersham, J.5, O'Connor, P.6, Bender, S.3 & Appelt,
K.A.7 Depts. of Res.1 & Dev.2 Pharmacology, Chemistry3, Biochemistry4, Crystallography5, Oncology6 &
Opthalmology Research7 Agouron Pharmaceuticals, San Diego, CA 92121.
We have discovered a novel carboxylate MMP inhibitor, AG3433, with potent activity against MMP-2, MMP-13
and MMP-3 (Ki's of 0.9, 3.3 & 19 nM, respectively, at pH 7.5) but not against MMP-7 and MMP-1 (Ki's of 4.5 &
14 µM, respectively). AG3433 is [congruent]15000-fold selective towards MMP-2 vs. MMP-1. High plasma
concentrations of AG3433 were observed after intraperitoneal (IP) administration in mice and after oral dosing in rats
and mice. Oral bioavailability in fed and fasted rats was 21 and 82%, respectively. AG3433 (25-500 mg/kg)
produced dose-dependent pharmacokinetics after oral administration with significant concentrations (>=100 ng/ml)
maintained in plasma up to 8 h after a single dose. AG3433 significantly decreased the development of B16-F10
lesions in the lungs of C57BL/6 mice after IV-tail implantation of tumor cells (p < 0.05). AG3433 also decreased the
growth of human colon and lung cancer tumors in nude mice after twice-daily oral administration (50 to 200
mg/kg/day) (p < 0.05). In summary, AG3433 has high selectivity for MMP-2, excellent pharmacokinetics after IP and
oral administration, and significant antitumor efficacy in vivo, supporting further study of AG3433 as a novel MMP
inhibitor with potential for improving cancer therapy. |
