Brain-Penetrating Reactivators of Organophosphate-InhibitedAcetylcholinesterase
Brian J. Lukey, James A. Romano, Salem Harry in Chemical Warfare Agents, 2019
A series of uncharged amidine oximes were synthesized and tested in vitro and for survival efficacy (Kalisiak et al., 2011, 2012). These showed potential as in vitro reactivators of AChE and butyrylcholinesterase. The survival experiments used a 30 min oxime pretreatment of mice against a soman surrogate and a 5 min post-treatment with oxime against a sarin surrogate, and both paradigms showed excellent survival efficacy of the amidine oximes (Kalisiak et al., 2011, 2012). However, these experimental paradigms were not designed to demonstrate that the enhanced survival was attributable to AChE reactivation in the brain. A subsequent report on these compounds concluded that the successful survival resulted from the enhanced nucleophilicity of the oxime provided by the amidine group and the ability to cross the BBB because of the zwitterionic nature of the compounds (Okolotowicz et al., 2014).
Nitric Oxide, Sepsis and the Heart
Malcolm J. Lewis, Ajay M. Shah in Endothelial Modulation of Cardiac Function, 2020
The differences between the constitutive and inducible NOS isoforms become important in pharmacological manipulations aimed at inhibiting the inducible production of NO, while allowing the low-level constitutive NOS to regulate homeostatic functions. The effectiveness of L-arginine derivatives in competitively inhibiting NOS provides a useful tool for the study of NO in biologic systems, and may provide a pharmacological mechanism to counteract a number of clinical scenarios where excess NO production is deemed detrimental. One such inhibitor, NG-nitro-L-arginine-methylester (L-NAME), is somewhat more selective in inhibiting NOS-3 than NOS-2, thus loosing some of its appeal for clinical application in sepsis. In addition, recent evidence shows that L-NAME, and other alkyl esters of arginine, interact with the muscarinic receptor (Buxton et al., 1993), confounding the results of these studies. All isoforms of NOS are inhibited to the same degree with NG-monomethyl-L-arginine (L-NMMA), and most of the relevant studies in sepsis were performed using this inhibitor. However, agents more selective for NOS-2 are currently under investigation. These compounds are non-amino acid guanidines, substituted isothioureas, amidines and substituted isoureas (Wolff and Lubeskie, 1995). These substances include aminoguanidine (Wu et al., 1995) and L-canavanine (Umans and Samsel, 1992), among others. While much is known about the enzymology of NOS, the field is still rapidly expanding, and more selective agents are continuously being discovered.
Molecular Recognition and Chemical Modification of Biopolymers — Two Main Components of Affinity Modification
Dmitri G. Knorre, Valentin V. Vlassov in Affinity Modification of Biopolymers, 1989
Applications of cross-linking techniques for the investigation of nucleoprotein complexes can be illustrated by the study of ribosome structure. For the identification of neighboring proteins within the ribosome a variety of bifunctional reagents was used, the most popular of which were bifunctional imidoesters (XV) and 2-iminothiolane (XVII). The latter reagent modifies primary amino groups of proteins forming amidine derivatives and introducing SH groups.
Characterizing and understanding the formation of cysteine conjugates and other by-products in a random, lysine-linked antibody drug conjugate
Published in mAbs, 2021
Difei Qiu, Yande Huang, Naresh Chennamsetty, Scott A. Miller, Michael Hay
Interestingly, the amidine moiety appeared stable in all of the lysine residue conjugates because the anticipated M + 1 counterparts of each individual identified lysine conjugates were not detected. The only amidine moiety prone to hydrolysis was located in the N-terminal conjugate (L1)E, under the same conjugation conditions. Despite the (L1)E having a high solvent accessibility, as illustrated in the 3D modeling structure in Figure 6a, some of the light chain lysine residues also exhibited high solvent accessibility, such as (L169)K with 94.1% SAA in Table 1. Thus, the hydrolysis of (L1)E to (L1)E + 1 was unlikely due to the solvent accessibility alone. The glutamic acid residue in (L1)E may also play an important role in mediating the hydrolysis of the amidine to amide, as illustrated in Figure 6b. The dissociated glutamate anion could intra-molecularly attack the protonated amidine moiety to form a seven-membered ring intermediate, which would undergo deamination followed by hydrolysis and ring opening to form the amide analog.
Targeting citrullination in autoimmunity: insights learned from preclinical mouse models
Published in Expert Opinion on Therapeutic Targets, 2021
Ylke Bruggeman, Fernanda M.C. Sodré, Mijke Buitinga, Chantal Mathieu, Lut Overbergh, Maria J.L. Kracht
To date, a variety of reversible and irreversible pan-PAD inhibitors and isozyme-specific PAD inhibitors have been described (Table 1). One of the first potent inhibitors developed is Cl-amidine [31]. Cl-amidine is an irreversible pan-PAD inhibitor that derives its effectivity from a reactive chloroacetamide warhead that covalently modifies the catalytic cysteine in the active site [31], and displays > 5-fold more potency for PAD1 and PAD4 than for PAD3 and PAD2 [32]. The efficacy of Cl-amidine as potential therapeutic has been proven in a variety of preclinical models, as discussed in detail later. However, a major drawback of Cl-amidine is its limited cellular bioavailability that results from a poor metabolic stability and membrane permeability [33]. This drawback was overcome by the design of BB-Cl-amidine that maintains the chloroacetamide warhead, but also holds a benzimidazole and biphenyl moiety limiting proteolysis and improving hydrophobicity, respectively [33]. Compared to Cl-amidine, BB-Cl-amidine is characterized by a superior cellular potency and an increased in vivo half-life (105 versus 15 minutes, approximately) [33]. It is often mistaken that BB-Cl-amidine is a potent PAD2 inhibitor. Although BB-Cl-amidine is slightly more potent to PAD2 compared to Cl-amidine, BB-Cl-amidine has higher potency for PAD1 and PAD4 than PAD3 and PAD2 [34]. BB-Cl-amidine has also proven to be highly effective in preventing autoimmunity in animals models [35,36].
Aldehyde oxidase mediated drug metabolism: an underpredicted obstacle in drug discovery and development
Published in Drug Metabolism Reviews, 2022
Siva Nageswara Rao Gajula, Tanaaz Navin Nathani, Rashmi Madhukar Patil, Sasikala Talari, Rajesh Sonti
Two strategies are available to reduce amide hydrolysis; one is by altering the acyl or amine group’s structure while keeping the amide group intact, and the other is by replacing the susceptible amide group with an isostere such as ureas, thioureas, hydrazides, and carbamates that are resistant to AO hydrolysis (Lepri et al. 2017). For instance, replacing amide in GDC-0834 with its isosteres such as sulfonamide, −NHCHCF3−, inverted and ternary amides reduced the hydrolysis rate (Figure 6(a) but diminished potency (Young et al. 2016). Other commonly used isosteres are amidine, guanidine, fluoroethylene, sulfonamide, cyclopropanamine, oxetan-3-amines, and trifluoroethylamine 5-membered heterocycles, like triazoles and oxadiazoles (Meanwell 2011).
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