2VNT

Urokinase-Type Plasminogen Activator Inhibitor Complex with a 1-(7- SULPHOAMIDOISOQUINOLINYL)GUANIDINE

Replaces:  2JDE

Summary for 2VNT

• Entry DOI: 10.2210/pdb2vnt/pdb
• Related: 1C5W 1C5X 1C5Y 1C5Z 1EJN 1F5L 1F92 1FV9 1GI7 1GI8 1GI9 1GJ7 1GJ8 1GJ9 1GJA 1GJB 1GJC 1GJD 1KDU 1LMW 1O3P 1O5A 1O5B 1O5C 1OWD 1OWE 1OWH 1OWI 1OWJ 1OWK 1SC8 1SQA 1SQO 1SQT 1U6Q 1VJ9 1VJA 1W0Z 1W10 1W11 1W12 1W13 1W14 2VIN 2VIO 2VIP 2VIQ 2VIV 2VIW
• Descriptor: UROKINASE-TYPE PLASMINOGEN ACTIVATOR, 1-({4-CHLORO-1-[(DIAMINOMETHYLIDENE)AMINO]ISOQUINOLIN-7-YL}SULFONYL)-D-PROLINE, SULFATE ION, ... (4 entities in total)
• Functional Keywords: upa, inhibitor complex, hydrolase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Secreted: P00749
• Total number of polymer chains: 6
• Total formula weight: 190263.27

Authors

Fish, P.V.,Barber, C.G.,Brown, D.G.,Butt, R.,Henry, B.T.,Horne, V.,Huggins, J.P.,McCleverty, D.,Phillips, C.,Webster, R.,Dickinson, R.P.,Collis, M.G.,King, E.,O'Gara, M.,McIntosh, F. (deposition date: 2008-02-07, release date: 2008-02-19, Last modification date: 2024-11-13)

Primary citation

Fish, P.V.,Barber, C.G.,Brown, D.G.,Butt, R.,Henry, B.T.,Horne, V.,Huggins, J.P.,McCleverty, D.,Phillips, C.,Webster, R.,Dickinson, R.P.,Collis, M.G.,King, E.,O'Gara, M.,McIntosh, F.
Selective Urokinase-Type Plasminogen Activator (Upa) Inhibitors 4. 1-(7-Sulphonamidoisoquinolinyl) Guanidines
J.Med.Chem., 50:2341-, 2007

PubMed Abstract: 1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids. The binding mode of these 1-isoquinolinylguanidines has been investigated by X-ray cocrystallization studies. uPA inhibitor 26 was selected for further evaluation based on its excellent enzyme potency (Ki 10 nM) and selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin). In vitro, compound 26 is able to inhibit exogenous uPA in human chronic wound fluid (IC50=0.89 microM). In vivo, in a porcine acute excisional wound model, following topical delivery, compound 26 is able to penetrate into pig wounds and inhibit exogenous uPA activity with no adverse effect on wound healing parameters. On the basis of this profile, compound 26 (UK-371,804) was selected as a candidate for further preclinical evaluation for the treatment of chronic dermal ulcers.

PubMed: 17447747
DOI: 10.1021/JM061066T

Experimental method

X-RAY DIFFRACTION (2.2 Å)