TMN 355

IC50: 1.52 nM

TMN 355 is a potent cyclophilin A inhibitor, approximately 27 times more potent than cyclosporin A.

In vitro: Remarkably, the PPIase inhibitory activities of derivative TMN 355 has increased up to 1.52 nM, , which are about 27 times more potent than that of CsA. The binding models the most potent inhibitor TMN 355 to CypA was generated by using AUTODOCK 324 and applying a Lamarckian genetic algorithm with a grid space set to be 0.375. Obviously, the binding model of compound 1 to CypA is very similar to that of TMN 355 to CypA, the planar fluorene ring inserts vertically into the hydrophobic gorge area in site A and then forms favorable hydrophobic interactions on account of these two types of appropriate terminal fragments, the acylurea linker of compounds 1 and TMN 355 adopted properly an orientation and interacted well with the saddle site. The interaction models also exhibited that both compounds 1 and TMN 355 form seven hydrogen bonds with residues Arg55, Gln63, and Asn102 in the saddle site. Furthermore, TMN 355 contains a chlorine atom that may impart hydrophobic interaction. The additional interaction was regarded as one of the key factors leading to 20 times potency improvement of TMN 355 compared with compound 1.

In vivo: So far, no study in vivo has been conducted.

Clinical trial: So far, no clinical study has been conducted.

Reference:
[1].  Ni S, Yuan Y, Huang J, Mao X, Lv M, Zhu J, Shen X, Pei J, Lai L, Jiang H, Li J. Discovering potent small molecule inhibitors of cyclophilin A using de novo drug design approach. J Med Chem. 2009 Sep 10;52(17):5295-8. doi: 10.1021/jm9008295.

Discovering potent small molecule inhibitors of cyclophilin A using de novo drug design approach.[Pubmed:19691347]

J Med Chem. 2009 Sep 10;52(17):5295-8.

This work describes an integrated approach of de novo drug design, chemical synthesis, and bioassay for quick identification of a series of novel small molecule cyclophilin A (CypA) inhibitors (1-3). The activities of the two most potent CypA inhibitors (3h and 3i) are 2.59 and 1.52 nM, respectively, which are about 16 and 27 times more potent than that of cyclosporin A. This study clearly demonstrates the power of our de novo drug design strategy and the related program LigBuilder 2.0 in drug discovery.

TMN355 is a potent chemical cyclophilin A inhibitor and reduces foam cell formation and cytokine secretion. TMN355 is used for atherosclerosis.

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