Potent and selective bicyclic lactam inhibitors of thrombin. Part 4: transition state inhibitors

Bachand, Benoit; Tarazi, Micheline; St‐Denis, Yves; Edmunds, Jeremy J.; Winocour, Peter D.; Leblond, Lorraine; Siddiqui, M. Arshad

doi:10.1016/s0960-894x(00)00636-3

Cited by 27 publications

(16 citation statements)

References 5 publications

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“…12), and b) 9 compounds 2b-f,h-k in the test set (Table 1 in ref. 13). c) Inhibitors of cathepsin K. [14] The full set of compounds in ref.…”

Section: Figurementioning

confidence: 99%

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Differentiating Serine and Cysteine Protease Mechanisms by New Covalent QSAR Descriptors

Shokhen¹,

Traube²,

Vijayakumar³

et al. 2011

ChemBioChem

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“…12), and b) 9 compounds 2b-f,h-k in the test set (Table 1 in ref. 13). c) Inhibitors of cathepsin K. [14] The full set of compounds in ref.…”

Section: Figurementioning

confidence: 99%

“…2a) [12] and 9 inhibitors in the test set (Fig. 2b), [13] contains W1 and W2 in combination with conventional 2D descriptors (Fig. 4a and Table S1 in SI).…”

mentioning

confidence: 99%

Differentiating Serine and Cysteine Protease Mechanisms by New Covalent QSAR Descriptors

Shokhen¹,

Traube²,

Vijayakumar³

et al. 2011

ChemBioChem

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“…Conversely, PA/pKa of TC(OH) dominates the CS covalent binding trend in cysteine proteases, so W2 plays an exclusive role there, while the contribution of W1 contribution is insignificant. EMBM was validated by QSAR analysis of a wide range of serine hydrolases (thrombin, [55,115] trypsin, [55,115] HNE, [24] and FAAH [54] ) and cysteine hydrolases (HRV 3C, [57] cathepsin K [116] and caspase 3 [117] ) with experimental pK i or pIC 50 values. It defines the opposite role of the W1 and W2 descriptors in the activity trend of the warheads: the activity of warheads towards a serine nucleophile increases with decreasing W1 values, and conversely a larger W2 descriptor defines a more active warhead towards a cysteine nucleophile.…”

Section: Embm: a Novel Mechanism-based Cadd Toolmentioning

confidence: 99%

From Catalytic Mechanism to Rational Design of Reversible Covalent Inhibitors of Serine and Cysteine Hydrolases

Shokhen

Hirsch

Khazanov

et al. 2014

Israel Journal of Chemistry

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Mechanistic studies of catalysis and the inhibition of serine and cysteine proteases afford new and sometimes surprising insights, challenging conventional dogmas in enzymology. The intrinsic source of the difference in the catalytic mechanisms of serine and cysteine hydrolases, the origin of the stability of the enzymeinhibitor complex in serine proteases, and the structures and mechanisms of catalysis and inhibition in cysteine proteases are not just intellectually interesting; our findings provide a mechanistic basis to understand the trend in the binding affinity of “warheads” of reversible covalent (reaction coordinate analogue, RCA) inhibitors. The theoretically derived covalent descriptors W1 and W2 differentiate serine and cysteine hydrolases and account for the energetic contribution of the new covalent bond in the enzymeinhibitor complex. The W1 and W2 descriptors are at the heart of our enzyme mechanism based method (EMBM); a new computer‐assisted drug design tool for the filtration of inhibitor warheads by activity. EMBM is unique because it accounts for both covalent and noncovalent interactions of RCA inhibitors with their target enzymes.

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“…Arginine mimetics with high basicity can be classified into α-amino acid arginine mimetics and arginine side-chain mimetics, usually lacking the carboxyl group. 10) [82], N-amidinopyrrolidines 55 and 56 [83,84] (Fig. 10) [67,[79][80][81], cyclohexylamine 54 (Fig.…”

Section: Arginine Mimetics In Thrombin Inhibitorsmentioning

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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Potent and selective bicyclic lactam inhibitors of thrombin. Part 4: transition state inhibitors

Cited by 27 publications

References 5 publications

Differentiating Serine and Cysteine Protease Mechanisms by New Covalent QSAR Descriptors

Differentiating Serine and Cysteine Protease Mechanisms by New Covalent QSAR Descriptors

From Catalytic Mechanism to Rational Design of Reversible Covalent Inhibitors of Serine and Cysteine Hydrolases

Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

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