Potent inhibition of thrombin by the newly synthesized arginine derivative No. 805. The importance of stereo-structure of its hydrophobic carboxamide portion

Okamoto, Shosuke; Hijikata, Akiko; Kikumoto, Ryoji; Tonomura, Shinji; Hara, Hiroto; Ninomiya, Kunihiro; Maruyama, Akira; Sugano, Mamoru; Tamao, Yoshikuni

doi:10.1016/0006-291x(81)91279-1

Cited by 254 publications

(130 citation statements)

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“…The piperidine moiety of MQPA leaves some extra space in the S2 pocket, which is ready to accept for example a methyl group in the equatorial 4-position, but is not large enough to accomodate a phenyl group [38]; axial piperidine substituents in the 2-position, such as a carboxylate group (even esterified or further elongated) should be easily acceptable, in agreement with experimental results [9,211. The piperidine moiety of NAPAP, in contrast, is much more tightly packed in the S2 subsite, leaving almost no space for substituents; however, insertion of further hydrogen bond donors (such as in piperazine) to saturate the buried carbonyl group of Ser214, or covalent bond connections to the naphthyl ring to stabilize the cage-like binding structure, might help to increase affinity.…”

Section: Discussionmentioning

confidence: 62%

“…The thrombin nomenclature used is based on topological equivalences to chymotrypsinogen such as suggested in [14]. and characterized mainly modeled after natural peptide substrates [7, 81, based on arginine [9] or benzamidine derivatives [lo, 111, or heterocyclic compounds [12, 131. Until now these synthetic inhibitors have either had to be inferred from natural protein substrates, or found through screening techniques with the help of quantitative structure/activity relationship methods.…”

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confidence: 99%

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Geometry of binding of the benzamidine‐ and arginine‐based inhibitors N^α‐(2‐naphthyl‐sulphonyl‐glycyl)‐dl‐p‐amidinophenylalanyl‐piperidine (NAPAP) and (2R,4R)‐4‐methyl‐1‐[N^α‐(3‐methyl‐1,2,3,4‐tetrahydro‐8‐quinolinesulphonyl)‐l‐arginyl]‐2‐piperidine carboxylic acid (MQPA) to human α‐thrombin

Bode

Turk

Stürzebecher

1990

European Journal of Biochemistry

125

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The X-ray crystal structure of the trypsin complex formed with N"-(2-naphthyl-sulphonyl-glycyl)-~~-pamidinophenylalanyl-piperidine (NAPAP) was determined with X-ray data to 0.18-nm resolution and crystallographically refined. NAPAP binds into the active site of trypsin in a quite compact form: the pamidinophenylalanine moiety of the D-stereoisomer binds into the specificity pocket; the glycyl group is hydrogen bonded with Gly216; the naphthyl group stands perpendicular to the indole moiety of Trp215; the piperidine ring is tightly packed between this naphthyl moiety and His.57; in consequence the carboxy-terminal amido bond of NAPAP is located in such a way that it is not susceptible to the active-site perfectly into the much more restricted active site of thrombin. The accommodation of the 5'-aryl moieties in the 'aryl-binding site' and of the piperidine rings in the S2 subsite of thrombin are particularly favourable. The preference of thrombin for distinctly substituted piperidine derivatives and its generally higher (compared with trypsin) affinity for benzamidine and arginine-based inhibitors can be accounted for by these thrombin inhibitor models.Thrombin, a trypsin-like serine proteinase, plays a central role in thrombosis and hemostasis. a-Thrombin converts fibrinogen into fibrin which forms part of the blood clot. It has also been implicated in platelet activation, activates other blood coagulation factors and interacts with various cells. The formation of clots in various thrombotic diseases has been attributed to the action of thrombin (see [l]). In cases of thrombotic disorder the quick supplementation with selective thrombin inhibitors (besides antithrombin 111) might offer an attractive means of therapy. Besides hirudin, an extremely potent and specific protein inhibitor from the medical leech [2 -61, various synthetic thrombin inhibitors have been foundCarrespondence to

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Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

Geometry of binding of the benzamidine‐ and arginine‐based inhibitors N^α‐(2‐naphthyl‐sulphonyl‐glycyl)‐dl‐p‐amidinophenylalanyl‐piperidine (NAPAP) and (2R,4R)‐4‐methyl‐1‐[N^α‐(3‐methyl‐1,2,3,4‐tetrahydro‐8‐quinolinesulphonyl)‐l‐arginyl]‐2‐piperidine carboxylic acid (MQPA) to human α‐thrombin

Bode

Turk

Stürzebecher

1990

European Journal of Biochemistry

125

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“…[15][16][17] On the other hand, many compounds having benzamidine or arginine moiety as a partial structure have been synthesized and their inhibitory effects on thrombin examined. [18][19][20][21][22][23] Argatroban (MD-805) proposed by Okamoto et al 18) is one of most potent synthetic thrombin inhibitors (K i ϭ1.9ϫ10 Ϫ8 M) and is clinically used. Complexes of human or bovine a-thrombin with synthetic arginyl peptides have been analyzed by X-ray diffraction studies.…”

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confidence: 99%

Amidino-Containing Schiff Base Copper(II) and Iron(III) Chelates as a Thrombin Inhibitor

Toyota

Sekizaki

Takahashi

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Thrombin is a trypsin-like serine proteinase that plays a critical role in the blood coagulation cascade. Thrombin converts fibrinogen into fibrin which forms part of the blood clot, 1,2) and activates other blood coagulation factors such as V, VIII, XIII, and protein C.3) Moreover, thrombin also activates blood platelets, 4,5) and acts as a mitogen for various cell types. [6][7][8] Thus, thrombin has become a special target in the design and development of antithrombotic agents.Various naturally occurring thrombin inhibitors have been found: hirudin (from the leech Hirudo medicinalis), 9,10) cyclotheonamide A, B, and nazumamide A (from the marine sponge Theonella sp.), [11][12][13][14] aeruginosin 298-A, aeruginosins 98-A and 98-B (from the blue-green alga Microcystis aeruginosa). [15][16][17] On the other hand, many compounds having benzamidine or arginine moiety as a partial structure have been synthesized and their inhibitory effects on thrombin examined. [18][19][20][21][22][23] Argatroban (MD-805) proposed by Okamoto et al. 18) is one of most potent synthetic thrombin inhibitors (K i ϭ1.9ϫ10 Ϫ8 M) and is clinically used. Complexes of human or bovine a-thrombin with synthetic arginyl peptides have been analyzed by X-ray diffraction studies. [24][25][26][27][28][29][30] The X-ray data suggested that the thrombin active site consists of the specificity (S1) pocket, the hydrophobic proximal pocket (P-pocket), and the hydrophobic distal pocket (D-pocket). The guanidino nitrogen atoms of inhibitors form a salt bridge with Asp189 (numbering of the thrombin amino acid residues is based on the chymotrypsinogen nomenclature introduced by Bode et al.) 24,28) in S1 pocket, and additional favorable interactions between the inhibitor and D-pocket or P-pocket enhance the inhibitory potency.Cationic organic molecules such as benzamidine and phenylguanidine derivatives are potent inhibitors of trypsin and trypsin-like enzymes, [31][32][33] owing to the electrostatic interaction between the cationic group of inhibitor and an anionic residue at S1 site in the trypsin active site. It is known that salicylaldehyde spontaneously forms a very stable Schiff base metal chelate with an a-amino acid and metal ion. Therefore, we designed and synthesized amidino-or guanidino-containing Schiff base metal chelates (Chart 1) as trypsin-like enzyme inhibitors. [34][35][36] The manifold compounds in the series of A and B can be prepared by changing the combination of salicylaldehyde derivatives, various aamino acids, and metal ions, respectively.Recently we proposed a new binding mode between trypsin active site and amidino-containing Schiff base metal chelate by X-ray diffraction study.37) The cationic amidino group of chelates was shown to form a salt bridge with the carboxylate of Asp189 in the S1 pocket of trypsin as expected. In addition, it was evidenced that the metal ion and the phenolic oxygen of the Schiff base contribute additional interactions with His57 and Ser195 of trypsin.In this report, the inhibitory effect of amidin...

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“…It is therefore suggested that impaired microvascular perfusion due to thrombin-induced microthrombi in the area surrounding the ischemic core contributes to the progression of ischemic lesions. Argatroban, a synthetic thrombin inhibitor (11,12), has been shown to prevent platelet-rich arterial thrombosis (13)(14)(15)(16)(17)(18).…”

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confidence: 99%

Effect of Argatroban on Microthrombi Formation and Brain Damage in the Rat Middle Cerebral Artery Thrombosis Model

Kawai

Umemura

Nakashima

1995

Japanese Journal of Pharmacology

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ABSTRACT-Ischemic cerebral infarcts induce hypercoagulation and microthrombosis in the surrounding region, thus leading to vascular occlusion. We determined whether microthrombi contribute to the spreading of ischemic lesions following thrombotic middle cerebral artery (MCA) occlusion and also determined whether argatroban, a selective thrombin inhibitor, reduces the formation of the microthrombi and the area of the ischemic lesions. The rat left MCA was occluded by a platelet-rich thrombus formed following the photochemical reaction between rose bengal and green light. Microthrombi were histologically identified in the left hemisphere. The extent of ischemic lesions and microthrombi containing fibrin increased in a timedependent manner after MCA occlusion. Argatroban inhibited the formation of microthrombi up to 3 hr after MCA occlusion; beyond 3 hr, it was ineffective. Argatroban also significantly (P<0.01) reduced the size of ischemic cerebral lesions at 6 hr after MCA occlusion. It is concluded that the formation of microthrombi contributes to the progression of ischemic lesions in the early stage. It is likely that thrombin generated following thrombotic MCA occlusion contributes to the progression of ischemic lesions by promoting the formation of microthrombi. Argatroban can reduce the formation of microthrombi and ischemic lesions in the early stage.

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Potent inhibition of thrombin by the newly synthesized arginine derivative No. 805. The importance of stereo-structure of its hydrophobic carboxamide portion

Cited by 254 publications

References 10 publications

Amidino-Containing Schiff Base Copper(II) and Iron(III) Chelates as a Thrombin Inhibitor

Effect of Argatroban on Microthrombi Formation and Brain Damage in the Rat Middle Cerebral Artery Thrombosis Model

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