1-Aminoisoquinoline as benzamidine isoster in the design and synthesis of orally active thrombin inhibitors

Rewinkel, J. B. M.; Lucas, Hans; Galen, P. J. M. van; Noach, A.B.J.; Dinther, Theo G. van; Rood, A.M.M.; Jenneboer, A.J.S.M.; Boeckel, C. A. A. Van

doi:10.1016/s0960-894x(99)00069-4

Cited by 56 publications

(29 citation statements)

References 9 publications

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“…None of the selected compounds has a stereocenter, in contrast with known inhibitors like BX 528, which has two chiral atoms. From the observation that the selected compounds resemble some aminoisoquinoline derivatives which were incorporated into thrombin inhibitors with the results of improved membrane transport and oral bioavailability (37,38), two additional aminoisoquinoline amino acids (molecular weight = 230 Da) were added to this set to compare them with those selected in the survey. These two additional compounds contain a chiral C and were assayed as a racemic mixture.…”

Section: Resultsmentioning

confidence: 99%

Aromatic Organic Compounds as Scaffolds for Metallocarboxypeptidase Inhibitor Design

2008

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We have identified and characterized a set of quinoline, naphthalene and quinazoline derivatives as inhibitors of metallocarboxypeptidases, a class of metal-dependent proteolytic enzymes. The aromatic organic compounds were selected from a high-throughput screening survey and, with some exceptions, showed a good correlation between inhibitory potency and docking energy value. The in vitro inhibition tests gave K(i) values in the lower micromolar range for metallocarboxypeptidases with different specificities, and a tendency to behave as more powerful inhibitors of CPB was observed for most of the compounds tested. The kinetic results were further analyzed by structural analysis via molecular docking. The most potent aromatic organic inhibitor docks to human CPB mostly through burial of its hydrophobic moiety deep into the enzyme's active site cleft and by interacting with the catalytic zinc ion. The significance of our results in designing inhibitors against disease-related CPs from the identified ligands is examined herein.

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Section: Resultsmentioning

confidence: 99%

Aromatic Organic Compounds as Scaffolds for Metallocarboxypeptidase Inhibitor Design

2008

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“…Rewinkel, et al have reported the use of 1-aminoisoquinoline as a benzamidine isostere in thrombin inhibitors [97]. The putative binding mode between Asp189 and the 1-aminoisoquinoline is bidentate as shown in Among factor Xa inhibitors, as in the thrombin field, the need to replace amidino groups with less basic P1 elements has been recognized.…”

Section: Incorporation Of Less Basic P1 Elementsmentioning

confidence: 99%

Perspectives on Factor Xa Inhibition

Rai¹,

Sprengeler²,

Elrod³

et al. 2001

CMC

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Blood coagulation involves a complex cascade of enzymatic reactions, ultimately generating fibrin, the basis of all blood clots. This cascade is comprised of two arms, the intrinsic and extrinsic pathways which converge at factor Xa to form the common pathway. Factor Xa activates prothrombin to thrombin, which in turn catalyzes the conversion of fibrinogen to fibrin. Recently, both natural and synthetic factor Xa inhibitors have shown promising pharmacological effects in animal models of thrombosis. Accordingly, factor Xa has emerged as a compelling target for pharmacological intervention and much recent effort has focused on selective and potent inhibition of this key enzyme. Factor Xa and other enzymes in the coagulation cascade belong to the trypsin-like serine protease family, the various members of which are involved in numerous physiological functions in the body. Hence, to avoid toxicity and adverse side effects, it is important to selectively inhibit the target enzyme. Achieving the needed selectivity has proved challenging due to the high degree of structural homology around the active site of this class of enzymes. This article provides a brief review of the strategies currently being employed to develop oral anticoagulants and, more specifically, the structural features of protein-ligand binding that have been utilized to achieve potency and selectivity toward factor Xa. Additionally, selected lead molecules will be discussed to highlight binding motifs used to attain both potency and selectivity in drug candidates.

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“…Ideally, those heterobicyclic P 1 -arginine mimetics would exhibit a range of pK a values, preserve important H-bonds and/or salt bridges with Asp189 and contribute additional hydrophobic interactions at S1. 14), 1-isoquinolineamine 94 [123] (Fig. Some of the bicyclic heteroaromatic P1 arginine mimics investigated (Fig.…”

Section: Heteroaromatic Mimetics Of Argininementioning

confidence: 99%

Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

Mašič

2006

CMC

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Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.

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1-Aminoisoquinoline as benzamidine isoster in the design and synthesis of orally active thrombin inhibitors

Cited by 56 publications

References 9 publications

Aromatic Organic Compounds as Scaffolds for Metallocarboxypeptidase Inhibitor Design

Aromatic Organic Compounds as Scaffolds for Metallocarboxypeptidase Inhibitor Design

Perspectives on Factor Xa Inhibition

Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

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