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. 2013 Oct 7;4(12):1152-7.
doi: 10.1021/ml400213v. eCollection 2013 Dec 12.

Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors

Rajeev Goswami  1 , Subhendu Mukherjee  1 , Gerd Wohlfahrt  2 , Chakshusmathi Ghadiyaram  1 , Jwala Nagaraj  1 , Beeram Ravi Chandra  1 , Ramesh K Sistla  1 , Leena K Satyam  1 , Dodheri S Samiulla  1 , Anu Moilanen  3 , Hosahalli S Subramanya  1 , Murali Ramachandra  1
Affiliations

Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors

Rajeev Goswami et al. ACS Med Chem Lett. .

Abstract

Matriptase belongs to trypsin-like serine proteases involved in matrix remodeling/degradation, growth regulation, survival, motility, and cell morphogenesis. Herein, we report a structure-based approach, which led to the discovery of sulfonamide and amide derivatives of pyridyl bis(oxy)benzamidine as potent and selective matriptase inhibitors. Co-crystal structures of selected compounds in complex with matriptase supported compound designing. Additionally, WaterMap analyses indicated the possibility of occupying a distinct pocket within the catalytic domain, exploration of which resulted in >100-fold improvement in potency. Co-crystal structure of 10 with matriptase revealed critical interactions leading to potent target inhibition and selectivity against other serine proteases.

Keywords: Matriptase; SAR; cancer; crystal structure; pyridyl dibenzimidamide.

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Figures

Figure 1
Figure 1
Crystallographic binding mode of benzamidine and a sulfate ion in matriptase catalytic domain (PDB code: 1EAX). Benzamidine showed a Ki ≈ 400 μM for matriptase inhibition.
Figure 2
Figure 2
Overlays: (a) docked model of 2 (Ki = 2.9 μM) and benzamidine (Ki ≈ 400 μM) binding mode; (b) docked model of 2 against crystallographic binding mode of 8 (Ki = 0.2 μM); (c) binding modes of 8 against that of benzamidine in surface mode depicting unstable WaterMap sites. Color codings for spherical (water) representations: red, crystallographic water molecules and lemon green, unstable water sites (ΔG > 2 kcal/mol); (d) Overlay of 8 and 10 crystallographic binding modes in matriptase catalytic domain along with mapped water molecules; (e) crystallographic binding mode of 10 in matriptase catalytic domain and structural basis for selectivity against thrombin (gray; PDB code: 1EB1(24)) and factor Xa (orange; PDB code: 1EZQ(25)); (f) crystallographic binding modes of 10 and 24 in matriptase catalytic domain.
Scheme 1
Scheme 1. Synthetic Scheme of 4,4′-(Pyridine-2,6-diylbis(oxy))dibenzimidamide Derivatives
Reagents and conditions: (a) K2CO3, DMF, 75 °C. (b) NH2OH·HCl, DIPEA, EtOH, 6 h, 85 °C. (c) Ac2O, AcOH, RT. (d) H2 at balloon pressure, 10% Pd/C, AcOH, 30 °C. (e) Zn powder, AcOH, 35 °C. (f) 4-Fluorobenzene sulfonylchloride, DIPEA, THF, RT.
Scheme 2
Scheme 2. Synthetic Scheme of 2,6-Bis(4-carbamimidoylphenoxy)nicotinamide Derivatives
Reagents and conditions: (a) K2CO3, DMF, 75 °C. (b) LiOH, THF, MeOH, 2 h, 15–20 °C. (c) tert-Butyl ((1R,4R)-4-aminocyclohexyl)carbamate, PyBop, DIPEA, DMF, RT. (d) Aq. NH2OH, EtOH, 4 h, 75 °C. (e) Ac2O in AcOH, RT. (f) Zn powder, AcOH, RT. (g) HCl(g)–EtOH at 5–10 °C.
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