Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors

NLR family proteins play important roles in innate immune response. NOD1 (NLRC1) activates various signaling pathways including NF-κB in response to bacterial ligands. Hereditary polymorphisms in the NOD1 gene are associated with asthma, inflammatory bowel disease, and other disorders. Using a high throughput screening (HTS) assay measuring NOD1-induced NF-κB reporter gene activity, followed by multiple downstream counter screens that eliminated compounds impacting other NF-κB effectors, 2-aminobenzimidazole compounds were identified that selectively inhibit NOD1. Mechanistic studies of a prototypical compound, Nodinitib-1 (ML130; CID-1088438), suggest that these small molecules cause conformational changes of NOD1 in?vitro and alter NOD1 subcellular targeting in cells. Altogether, this inaugural class of inhibitors provides chemical probes for interrogating mechanisms regulating NOD1 activity and tools for exploring the roles of NOD1 in various infectious and inflammatory diseases.     

Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors

The discovery of selective cyclooxygenase-2 (COX-2) inhibitors represents a major achievement of the efforts over the past few decades to develop therapeutic treatments for inflammation. To gain insights into designing new COX-2-selective inhibitors, we address the energetic and structural basis for the selective inhibition of COX isozymes by means of a combined computational protocol involving docking experiment, force field design for the heme prothetic group, and free energy perturbation (FEP) simulation. We consider both COX-2- and COX-1-selective inhibitors taking the V523I mutant of COX-2 to be a relevant structural model for COX-1 as confirmed by a variety of experimental and theoretical evidences. For all COX-2-selective inhibitors under consideration, we find that free energies of binding become less favorable as the receptor changes from COX-2 to COX-1, due to the weakening and/or loss of hydrogen bond and hydrophobic interactions that stabilize the inhibitors in the COX-2 active site. On the other hand, COX-1-selective oxicam inhibitors gain extra stabilization energy with the change of residue 523 from valine to isoleucine because of the formations of new hydrogen bonds in the enzyme-inhibitor complexes. The utility of the combined computational approach, as a valuable tool for in silico screening of COX-2-selective inhibitors, is further exemplified by identifying the physicochemical origins of the enantiospecific selective inhibition of COX-2 by -substituted indomethacin ethanolamide inhibitors.     

Reactions of 1-methyl-derivatives of 2-oxo-1,2,3,4-tetrahydropyrimidine with phosphorus pentachloride and phosphorus oxychloride

In the reaction of 4-phenyl- and 4,6-diphenyl-1-methyl-2-oxo-5-ethoxycarbonyl-1,2,3,4-tetrahydropyrimidines with phosphorus pentachloride, oxidation and dealkylation takes place in addition to chlorination and as a result one obtained 4-phenyl- and 4,6-diphenyl-1-methyl-5-ethoxycarbonyl-2-pyrimidones and also 4-phenyl-, (4,6-diphenyl)-5-ethoxycarbonyl-2-chloropyrimidines. 1,6-Dimethyl-2-oxo-4-phenyl-5-ethoxycarbonyl-1,2,3,4-tetrahydropyrimidine in the same reaction gives 1-methyl-2-oxo-4-phenyl-5-ethoxycarbonyl 6-dichloromethyl-1,2,3,4-tetrahydropyrimidine, together with 6-chloromethylene- and 6-dichloromethylene-1-methyl-2-oxo-4-phenyl-5-chloro-5-ethoxycarbonylhexahydropyrimidines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 668–671, May, 1987.     

Synthesis and biological evaluation of 1,2,3,4-tetrahydroisoquinoline derivatives as potent and selective M2 muscarinic receptor antagonists.

A series of 1,2,3,4-tetrahydroisoquinoline derivatives containing the 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton were prepared and evaluated for their in vitro binding affinities to muscarinic receptors and for antagonism of bradycardia in vivo. Among them, compound 3f had the highest affinity for M2 muscarinic receptors in the heart (pKi = 9.1) with low affinity for M3 muscarinic receptors in the submandibular gland. A structure-activity relationship (SAR) study suggested that the benzene ring fused piperidine and the alkyl linker chain length are crucially important for increased M2 affinity.     

Synthesis and biological evaluation of 3-amino-2-pyrones as selective cyclooxygenase-1 (COX-1) inhibitors

A group of 3-amino-2-pyrones were synthesized and their biological activities were evaluated for inhibiting cyclooxygenase（COX） activity.This study has led to the identification of COX-1-selective inhibitors.Among the tested compounds,the compound 5j exhibited the most potent COX-1 inhibitory activity(IC₅₀ = 19.32μg/mL) and COX-1 selectivity index（SI = 41.98）.     

Development of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives as selective inhibitors of glucosylceramide metabolism in man

In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a wide variety of lipophilic mono- and difunctionalized 1-deoxynojirimycin derivatives. The compounds reported here are lipophilic iminosugar based on lead compound 4, a potent inhibitor of the three enzymes involved in the metabolism of the glycosphingolipid glucosylceramide. Iminosugar-based inhibitors of glucosylceramide synthase, one of these three enzymes, have attracted increasing interest over the past decade due to the crucial role of this enzyme in glycosphingolipid biosynthesis. Combined with the fact that an increasing number of pathological processes are being linked to excessive glycosphingolipid levels, glucosylceramide synthase becomes a very attractive therapeutic and research target. Our results presented here demonstrate that relocating the lipophilic moiety from the nitrogen atom to other positions on the 1-deoxynojirimycin ring system does not lead to a more potent or selective inhibitor of glucosylceramide synthase. The beta-aza-C-glycoside analogue (17) retained the best inhibitory potency for glucosylceramide synthase and is a more potent inhibitor than the therapeutic agent N-butyl-1-deoxynojirimycin (3), marketed as treatment for Gaucher disease under the commercial name Zavesca.     

Design,synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors

The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms（MPNs）. At present, there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic. In this paper, a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design, synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib. Among them, 21 b exhibited high ...     

Design of new selective inhibitors of cyclooxygenase-2 by dynamic assembly of molecular building blocks

A method of dynamically assembling molecular building blocks - DycoBlock - has been proposed and tested by Liu et al. This method is based on multiple-copy stochastic dynamics simulation in the presence of a receptor molecule. In this method, a novel algorithm was used to dynamically assemble the molecular building blocks to form candidate compounds. Currently, some new improvements have been incorporated into DycoBlock to make it more efficient. In the new version of DycoBlock, the binding energy and solvent accessible surface area (SASA) can be used to screen the resulting compounds. A simple clustering algorithm based on molecular similarity was developed and used to classify the remaining compounds. The revised DycoBlock was tested by breaking SC-558 - a selective inhibitor of cyclooxygenase-2 (COX-2) - into building blocks and reassembling them in the active site of the enzyme. The accuracy of recovery grew to 58.8% while it was only 16.7% in the previous version. Then, thirty-three kinds of molecular building blocks were used in the design of novel inhibitors and the investigation of diversity. As a result, a total of 1441 compounds was generated with high diversity. After the first screening procedure, there remained 864 reasonable compounds. The results from clustering indicate that the structural motifs in the diarylheterocycle class of COX-2-selective inhibitors have been generated using the revised DycoBlock, and their binding modes were investigated.     

Discovery of novel selective serotonin reuptake inhibitors through development of a protein-based pharmacophore

The serotonin transporter (SERT), a member of the neurotransmitter sodium symporter (NSS) family, is responsible for the reuptake of serotonin from the synaptic cleft to maintain neurotransmitter homeostasis. SERT is established as an important target in the treatment of anxiety and depression. Because a high-resolution crystal structure is not available, a computational model of SERT was built based upon the X-ray coordinates of the leucine transporter LeuT, a bacterial NSS homologue. The model was used to develop the first SERT structure-based pharmacophore. Virtual screening (VS) of a small molecule structural library using the generated SERT computational model yielded candidate ligands of diverse scaffolds. Pharmacological analysis of the VS hits identified two SERT-selective compounds, potential lead compounds for further SERT-related medication development.     

Preparation of 3-arylmethylindoles as selective COX-2 inhibitors

The 3-arylmethylation of indoles using TMSOTf/Et₃SiH with a wide variety of substituted benzaldehydes has been accomplished. Under these mild Lewis acid mediated reductive conditions, it was demonstrated that indoles bearing both 6-MeSO₂ and 2-methyl substituents could be 3-arylmethylated in good to excellent yields to afford the corresponding 3-arylmethyl indoles, effective as selective COX-2 inhibitors. In addition, the viability of this method for the reductive alkylation of indoles by ketones was demonstrated and shown to be C-3 regioselective. For indoles bearing both a 6-MeSO₂ and 2-cyano substituent where this indole reductive alkylation methodology was unsuccessful, an unprecedented Pd(0) mediated arylorganozinc coupling with the requisite substituted 3-methylcarbonatomethylindole proved successful in affording the desired 2-cyano-6-MeSO₂-3-arylmethylindoles effective as selective COX-2 inhibitors.     

Synthesis and oxidative aromatization of 5-acetyl-2-cyanoimino-6-methyl-4-phenyl-1,2,3,4-tetrahydropyrimidine with manganese dioxide

The synthesis of 5-acetyl-2-cyanoimino-6-methyl-4-phenyl-1,2,3,4-tetrahydropyrimidine has been carried out by reaction of N-[(tosyl)(phenyl)methyl]-N′-cyanoguanidine with acetylacetone in the presence of sodium hydride with subsequent acid catalyzed dehydration of the 4-hydroxy-2-imino-hexahydropyrimidine obtained. The oxidative aromatization of the tetrahydropyrimidine synthesized using manganese dioxide has been studied. It was found that the products formed depend on the reaction temperature and are either 5-acetyl-2-carbamoylamino-4-methyl-6-phenylpyrimidine or 5-acetyl-2-amino-4-methyl-6-phenylpyrimidine or a mixture of both.     

Synthesis of 2-quinolinecarboxamide derivatives as potential HDAC inhibitors

Inhibition of histone deacetylase activity appears as an original and effective approach for the treatment of cancer. A series of novel quinoline-containing derivatives has been synthesized and found that some of these compounds possess nanomolar histone deacetylase inhibitory activity.     

Synthesis of novel curcumin analogues and their evaluation as selective cyclooxygenase-1 (COX-1) inhibitors

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that cyclooxygenase-1 (COX-1) plays an important role in inflammation and carcinogenesis. In order to find more selective COX-1 inhibitors a series of novel curcumin derivatives was synthesized and evaluated for their ability to inhibit this enzyme using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production. All curcumin analogues showed a higher rate of COX-1 inhibition. The most potent curcumin compounds were (1E,6E)-1,7-di-(2,3,4-trimethoxyphenyl)-1,6-heptadien-3,5-dione (4) (COX-1: IC(50) = 0.06 microM, COX-2: IC(50) > 100 microM, selectivity index>1666) and (1E,6E)-methyl 4-[7-(4-methoxycarbonyl)phenyl]-3,5-dioxo-1,6-heptadienyl]benzoate (6) (COX-1: IC(50) = 0.05 microM, COX-2: IC(50) > 100 microM, selectivity index > 2000). Curcumin analogues therefore represent a novel class of highly selective COX-1 inhibitors and promising candidates for in vivo studies.     

Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2

3-halo-4,5-dihydroisoxazoles are attractive warheads for the selective inhibition of nucleophilic active sites in biological systems. A series of 3-bromo-4,5-dihydroisoxazole compounds were prepared and tested for their ability to irreversibly inhibit human transglutaminase 2 (TG2), an enzyme that plays an important role in the pathogenesis of diverse disorders including Celiac Sprue and certain types of cancers. Several compounds showed high specificity for human TG2 (k(inh)/K(I) > 2000 min(-1)M(-1)) but essentially no reactivity (k < 1 min(-1)M(-1)) toward physiological thiols such as glutathione. The pharmacokinetic and pharmacodynamic properties of a prototype dihydroisoxazole inhibitor, 1b, were evaluated; in mice the compound showed good oral bioavailability, short serum half-life and efficient TG2 inhibition in small intestinal tissue, and low toxicity. It also showed excellent synergism with N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU, carmustine) against refractory glioblastoma tumors in mice. A fluorescent dihydroisoxazole inhibitor 5 facilitated microscopic visualization of TG2 endocytosis from the extracellular surface of HCT-116 cells. Together, these findings demonstrate the promise of dihydroisoxazole compounds as probes for the biology of TG2 and its role in human disease.