Discovery of Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP)-13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach

Abstract

On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, 31f exhibited excellent potency for MMP-13 (IC = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition.

Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors

“…35 With the goal of further expanding the chemical diversity, we next investigated the potential of ZBGs. In addition to accessing unique structure space, we expected that the inclusion of non-carboxylic acid-based ZBGs could impart useful biological properties such as improved pharmacokinetics or permeability into cartilage matrix.…”

“…In the course of the study of the MMP inhibitor without a ZBG aimed at the designing new P1" in our laboratory, we have found that introduction of a small aryl group into the 5-position of the thienopyrimidine-2-carboxamide structure resulted in the excellent potency/selectivity profile (Figure 6). 35 Thus, the 5-arylthienopyrimidine derivative 55 with a benzene ring directly attached to the thiophene ring not only enhanced the inhibitory activity but also improved the selectivity profile compared to the quinazoline 3 ( Table 2, 3 vs 55). Therefore, in a series of derivatives containing ZBGs, small aromatic rings were P1" substituents of choice for the inhibition of MMP-13 (Table 2, 37 and 56).…”

“…As a result, improvement of potency has been achieved by the combination of a simple linker with a triazole group as a ZBG ( Table 2, 56). 35 However, in contrast to the triazole ZBG series 56, incorporation of the 5-arylthienopyrimidine-type P1" group into the triazolone 35 was not proved to be well tolerated (Table 2， 35 vs 37). Probably, coupled with the size of the triazolone ZBG group, introduction of a rigid biphenyl P1' linker and a sulfonyl group resulted in a small shift of the pyrimidine-4-one-2-carboxamide core structure toward the primed side of the binding site, which would result in a significant loss in potency.…”

“…Installation of a variety of 5-membered heterocycles linked via a piperazine spacer (45a-e) was performed using divergent synthetic strategy whereby various potential ZBGs could be introduced on a common As shown in Scheme 7, ester 10 was subjected to aminolysis by treatment with amine 52 35 in EtOH to afford compound 53, which was converted to 1,2,4-triazole 54 under acidic condition.…”

“…[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Recently, we described highly selective MMP-13 inhibitors, which do not bind the catalytic zinc ion ( Figure 1). [33][34][35][36] The inhibitors possess a pyrimidin-4-one-2-carboxamide core, which binds effectively to the primed regions (S1') of the catalytic active site 36,37 , and the fused pyrimidine carboxamide systems were successfully applied to other selective MMP-13 inhibitors. [38][39][40] Among the previously synthesized compounds in our laboratories, promising derivatives, quinazoline-2-carboxamide and thienopyrimidine-2-carboxamide based MMP-13 inhibitors, as exemplified by 1 and 2, were identified, which exhibit potent inhibition of MMP-13, but weak inhibitory activity toward other members of the MMP family.…”