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

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…At Takeda, Nara and co‐workers applied the strategy of connecting a zinc‐binding group to two of their previously described non‐zinc‐binding MMP‐13 inhibitors …”

“…Appealing properties, such as high stability in rat and human liver microsomes, low inhibition of cytochrome P450 3A4, and low toxicity, were found for 58 . Shortcomings occurred, with an oral bioavailability of less than 5 % in rats, most likely due to low solubility and permeability . A superposition study of the cocrystal structures of MMP‐13 complexed to 4‐oxo‐3,4‐dihydroquinazoline and triazole derivatives, previously identified in a high‐throughput screening campaign, yielded the hybrid inhibitor 59 (Figure ), with an IC 50 value of 0.2 n m against MMP‐13, that could be cocrystallized within the receptor (Figure ) .…”

Development of matrix metalloproteinase-13 inhibitors – A structure-activity/structure-property relationship study

“…CYP 3A4 inhibition has also been responsible for the termination of the development of MMP-13 inhibitors. 28 Therefore, we further assessed the in vitro inhibition of CYP 1A2, 2C9, 2D6, and 3A4 for the compounds 2 , 28 and 30 - 32 (Table 9) at a concnetration of 10 μM. The lead compound 2 inhibited CYP 2C9 and 3A4 at levels of 60 and 16%, respectively.…”

“…30,31 Pyrimidine-2-carboxamide-4-one-based inhibitors have exhibited poor bioavailability, low volume of distribution, poor metabolic stability, and/or P450 3A4 inhibition. 28 Obtaining appropriate kinetic solubilities for MMP- 13 inhibitors has proved challenging. 12, 32 Due to design considerations based on activity profiles and prior data, several of the compounds described herein avoid many of these pitfalls, particularly poor solubility and metabolic stability as well as the potential for nephrotoxicity and generation of reactive metabolites.…”

Targeted Fluoro Positioning for the Discovery of a Potent and Highly Selective Matrix Metalloproteinase Inhibitor

“…Later developments led to allosteric binders, occupying the selectivity loop within the S 1 ′ pocket, sparing the interaction to the zinc ion . Equipping selective allosteric inhibitors with weaker metal‐chelating groups, such as carboxylic acid for example, can improve the potency of the inhibitors while maintaining the selectivity profile …”