Development of plasma kallikrein selective inhibitors

Okada, Yoshio; Tsuda, Yuko; Tada, Mayako; Wanaka, Keiko; Hijikata-Okunomiya, Akiko; Okamoto, Utako; Okamoto, Shosuke

doi:10.1002/(sici)1097-0282(1999)51:1<41::aid-bip5>3.0.co;2-y

Cited by 18 publications

(14 citation statements)

References 43 publications

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“…However, neither of the basic moieties, tranexamic acid and homoarginine, found in the inhibitors, has so far been identified as a building block of selective inhibitors of thrombin or other closely related enzymes involved in the coagulation cascade. Only certain plasma kallikrein-selective inhibitors were reported to contain tranexamic acid (5). Because the tranexamic acid building blocks in 8-1 and 8-5 can be replaced not only by L-arginine (7-4 and 7-8) but also by L-alanine (7-1) without dramatically impairing inhibitory activity, we were inclined to assume that tranexamic acid is not a superior candidate for S1 site occupation.…”

Section: Resultsmentioning

confidence: 99%

Thrombin inhibitors identified by computer-assisted multiparameter design

Riester

Wirsching

Salinas

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Here, we present a series of thrombin inhibitors that were generated by using powerful computer-assisted multiparameter optimization process. The process was organized in design cycles, starting with a set of randomly chosen molecules. Each cycle combined combinatorial synthesis, multiparameter characterization of compounds in a variety of bioassays, and algorithmic processing of the data to devise a set of compounds to be synthesized in the next cycle. The identified lead compounds exhibited thrombin inhibitory constants in the lower nanomolar range. They are by far the most selective synthetic thrombin inhibitors, with selectivities of >100,000-fold toward other proteases such as Factor Xa, Factor XIIa, urokinase, plasmin, and Plasma kallikrein. Furthermore, these compounds exhibit a favorable profile, comprising nontoxicity, high metabolic stability, low serum protein binding, good solubility, high anticoagulant activity, and a slow and exclusively renal elimination from the circulation in a rat model. Finally, x-ray crystallographic analysis of a thrombin-inhibitor complex revealed a binding mode with a neutral moiety in the S1 pocket of thrombin.crystallographic structure ͉ drug design ͉ early adsorption ͉ toxicity ͉ genetic algorithm

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Section: Resultsmentioning

confidence: 99%

Thrombin inhibitors identified by computer-assisted multiparameter design

Riester

Wirsching

Salinas

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…by guest www.bloodjournal.org From times was performed by the use of the very specific inhibitor PKSI-527. 13 These data suggest that, unlike other plasma contact system proteins, inhibition of plasma kallikrein, like PRCP depletion or inhibition, increases arterial thrombosis risk. This observation is relevant to the developing clinical use of plasma kallikrein inhibitors to treat angioedema and reduce bleeding in cardiopulmonary bypass.…”

Section: Discussionmentioning

confidence: 99%

“…PKSI-527 was from Dr Yoshio Okada, Kobe Gakuin University, Kobe, Japan. 13 Mouse anti-human antibody to thrombomodulin was obtained from Santa Cruz Biotechnology (sc-13164).…”

Section: Methodsmentioning

confidence: 99%

“…11 PRCP also degrades ␣-melanocyte stimulating hormone (␣-MSH [1][2][3][4][5][6][7][8][9][10][11][12][13] ) to its inactive ␣-MSH [1][2][3][4][5][6][7][8][9][10][11][12] form by cleaving its C-terminal Val. 12 ␣-MSH [1][2][3][4][5][6][7][8][9][10][11][12][13] stimulates an anorexigenic response. PRCP gene-trap mice are lean because of reduced hypothalamic ␣-MSH 1-13 degradation.…”

Section: Introductionmentioning

confidence: 91%

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Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis

Adams¹,

LaRusch²,

Stavrou³

et al. 2011

Blood

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“…TKI was shown to inhibit human tissue kallikrein in vitro with K i =0.7 mM, but it did not inhibit human plasma kallikrein at concentrations 1000 fold higher than its K i value (Portaro et al, 1997). PKSI-527 in its turn, inhibited plasma kallikrein in vitro with K i value of 0.81 mM, while it inhibited tissue kallikrein with K i values higher than 500 mM (Okada et al, 1999). Assuming that both TKI and PKSI-527 exhibit the same speci®ty in vitro and in vivo, our results suggest a predominant role of tissue kallikrein in the mouse writhing response.…”

Section: Discussionmentioning

confidence: 93%

Evidence for activation of the tissue kallikrein‐kinin system in nociceptive transmission and inflammatory responses of mice using a specific enzyme inhibitor

Emim¹,

Souccar²,

Castro³

et al. 2000

British J Pharmacology

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1 The pharmacological activity of phenylacetyl-Phe-Ser-Arg-N-(2,4-dinitrophenyl)-ethylenediamine (TKI), a tissue kallikrein speci®c inhibitor, was assessed using models of nociception and in¯ammation in mice. 2 Injection of TKI (13.6 ± 136 mmol kg 71 , i.p. or 41 ± 410 mmol kg 71 , s.c.) produced a dose-related inhibition of the acetic acid-induced writhes (by 37 to 85% or 34 to 80%, respectively). The antinociceptive activity of TKI (41 mmol kg 71 , i.p.) was maximal after 30 min injection and lasted for 120 min. The e ect was unaltered by pretreatment with naloxone (8.2 mmol kg 71 , s.c.) or bilateral adrenalectomy. 3 TKI (41 and 136 mmol kg 71 , i.p.) produced a dose-related decrease of the late phase of formalininduced nociception by 79 and 98%, respectively. At 136 mmol kg 71 , i.p., TKI also shortened the duration of paw licking in the early phase by 69%. TKI (41 and 136 mmol kg 71 , i.p.) also reduced the capsaicin-induced nociceptive response (by 51 to 79%). 4 TKI (41 mmol kg 71 , i.p. or 410 mmol kg 71 , s.c.) reduced the oedematogenic response, from the second to the ®fth hour after carrageenin injection by 36 to 30% or by 47 to 39%, respectively. 5 Pretreatment with TKI (41 mmol kg 71 , i.p.) reduced the capsaicin-induced neurogenic in¯ammation in the mouse ear by 54%. 6 It is concluded that TKI presents antinociceptive and antiin¯ammatory activities mediated by inhibition of kinin formation by tissue kallikrein in mice. The results also indicate that the tissue kallikrein-dependent pathway contributes to kinin generation in nociceptive and in¯ammatory processes in mice.

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Development of plasma kallikrein selective inhibitors

Cited by 18 publications

References 43 publications

Thrombin inhibitors identified by computer-assisted multiparameter design

Thrombin inhibitors identified by computer-assisted multiparameter design

Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis

Evidence for activation of the tissue kallikrein‐kinin system in nociceptive transmission and inflammatory responses of mice using a specific enzyme inhibitor

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