Kurt A. Josef’s research while affiliated with Albert Einstein College of Medicine and other places

... Conversely, reduction of neuronal histamine release following injection of immepip, an H3R agonist, elicited amnesic effects [28]. Several studies using different H3R antagonists confirmed and expanded these observations [29][30][31][32][33][34]. However, these studies were performed using the habituation/dishabituation paradigm in rats using short inter trial intervals (40-120 min), therefore they were not suitable to explore putative differential effects on short-and long-term memories. ...

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Short- and Long-Term Social Recognition Memory Are Differentially Modulated by Neuronal Histamine

... Thus, one strategy is the replacement of amino acids in these di-or tripeptide inhibitors (e.g. aldehydes [115], leupeptin (Ac-Leu-Leu-Arg-H), MDL28170 (Z-Val-Phe-H)) and thus improving at least the stability (Figure 3). ...

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Modulators of calpain activity: inhibitors and activators as potential drugs

... 20 PFMKs are usually obtained by incorporating the corresponding uoroalcohol into a peptide sequence, by a solution coupling with the carboxylic acid terminus of a peptide, followed by alcohol oxidation. 4,[21][22][23][24][25] However, this methodology is limited to peptide sequences that either do not contain crossreacting sidechain groups, have their sidechains orthogonally protected, or do not contain oxidation sensitive residues such as Cys, Met, Trp or Tyr. Furthermore, the solubility issue associated with fully protected amino acids in solid phase peptide synthesis (SPPS) and the racemisation possibilities at the Cterminal amino acid limit the capacity of this synthetic procedure. ...

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An improved method for the incorporation of fluoromethyl ketones into solid phase peptide synthesis techniques

... There are a limited number of reported selective TrkA receptor tyrosine kinase inhibitors in the literature (Figure 1) [7][8][9]. Developed by Cephalon (now a group member of Teva Pharmaceutical Industries Ltd.), lestaurtinib (CEP-701) is a potent multitargeted tyrosine kinases inhibitor targeting mainly TrkA, Flt3, and JAK2 and is in clinical trials for the treatment of myeloproliferative disorders [10,11]. More recently, Cephalon disclosed indenopyrrolocarbazole 12a as a potent and selective TrkA inhibitor displaying antitumor properties [12]. ...

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Identification of a Novel Series of Potent TrkA Receptor Tyrosine Kinase Inhibitors

... Alternatively, treatment of CMT-64 with the calcium ionophore, ionomycin, increased release of FL and ~18 kDa IL-33 ( Fig. S3a and b) concurrent with cell damage (Fig. S3c). Broad-spectrum protease inhibitors implicated cysteine protease activity in the processing of IL-33 in CMT-64 cells (Figs 3c, S8) and indeed calpain inhibitors (calpeptin, calpain inhibitors-I, -II and -III 25,26 ), as well as the calcium chelator BAPTA-AM 27 , completely inhibited the generation of ~18 kDa IL-33 (Figs 3d, S3d and S9). Processing of endogenous IL-33 in primary normal human bronchial epithelial cells (NHBE) was also dependent on calpain activity (Fig. S3e). ...

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Interleukin-33 is activated by allergen- and necrosis-associated proteolytic activities to regulate its alarmin activity during epithelial damage

... However, these m-PFMKs did not show much selectivity, as they were comparably or ever more potent towards Cat-L [76]. A more exhaustive SAR analysis about the dipeptidyl derivatives having a m-FMK warhead was provided, later on, by Chatterjee's research group in 1996/97 [77,78]. While previous studies had shown that calpain(s) cleave at peptide bonds of amino acids preceded by a Leu residue and therefore Leu or other branched amino acids (e.g., Val) are preferred at the P2 site [79], Chatterjee's works showed that the P 1 side chain and the N-terminal capping group have a notable effect on the potency and selectivity towards recombinant human calpain I. ...

Reference:

Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry

... accession number: Q5S007, accessed on 14 August 2020). The X-ray crystal structure of mixed lineage kinase 1 (MLK1) in complex with a potent inhibitor [37] served as a template to build 3D atomic coordinates of the target protein. The reason for this selection is that MLK1 had the highest score in the amino-acid sequence alignment with the kinase domain of the G2019S mutant (residues 1872-2134) via the basic local alignment search tool (BLAST) [38]. ...

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Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2

... The compounds 2H-benzo[h]cinnolin-3-ones and 3H-benzo[f ]cinnolin-2-ones exhibited high H 3 receptor binding affinity with excellent selectivity against the H 1 R, H 2 R and H 4 R subtypes of histamine receptor. Modification to the linker/amine region of the pharmacophore resulted in ±49 as a mixture of diastereoisomers (Figure 26), which showed improved metabolic stability and rat pharmacokinetics following oral administration ( [55] and references therein). The cinnoline scaffold turned out to be a useful building block in designing compounds targeting histamine receptor H3. ...

Reference:

Cinnoline Scaffold—A Molecular Heart of Medicinal Chemistry?

... This amination reaction was used to formally synthesize the functional antagonist of the histamine H 3 receptor (Scheme 3 C). [18] The alkylation of 1 m with 2 b under the optimized conditions provided 9 in 62 % yield. Heterocyclic product 11 was obtained after the deprotection of 9 followed by the cyclization of 10 with hydrazine. ...

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Direct α‐Tertiary Alkylations of Ketones in a Combined Copper–Organocatalyst System

... Hudkins et al. synthesized of pyridazinone derivatives and determined their histamine H 3 receptor inverse agonists. Compound 150 was reported as a lead candidate demonstrating potent in vivo functional H 3 R antagonism in the rat dipsogenia model [173]. Bruel et al. reported compound 151 as a promising DYRK1A inhibitor with IC 50 value of 0.6 mM [174]. ...

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The therapeutic journey of pyridazinone