title: Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.
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.
authors: Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK. paul.fish@pfizer.com
authors: Paul V
authors: PV
authors: Fish
authors: Christopher G
authors: CG
authors: Barber
authors: David G
authors: DG
authors: Brown
authors: Richard
authors: R
authors: Butt
authors: Michael G
authors: MG
authors: Collis
authors: Roger P
authors: RP
authors: Dickinson
authors: Brian T
authors: BT
authors: Henry
authors: Valerie A
authors: VA
authors: Horne
authors: John P
authors: JP
authors: Huggins
authors: Elizabeth
authors: E
authors: King
authors: Margaret
authors: M
authors: O'Gara
authors: Dawn
authors: D
authors: McCleverty
authors: Fraser
authors: F
authors: McIntosh
authors: Christopher
authors: C
authors: Phillips
authors: Robert
authors: R
authors: Webster
mesh_terms: D000208:Acute Disease; D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002908:Chronic Disease; D018360:Crystallography, X-Ray; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012867:Skin / Q000293:injuries; D012871:Skin Diseases / Q000201:enzymology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013552:Swine; D014456:Ulcer / Q000201:enzymology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014945:Wound Healing / Q000187:drug effects
chemical_list: C520855:2-(((4-chloro-1-guanidino-7-isoquinolinyl)sulfonyl)amino)isobutyric acid; D000897:Anti-Ulcer Agents; D006146:Guanidines; D011804:Quinolines; D013449:Sulfonamides; D014568:Urokinase-Type Plasminogen Activator