Analogues Of 1a Research Articles

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Anti-alphavirus Activity.

Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (1a) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of 1a that varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of Chikungunya (CHIKV) nsP2 protease and viral replication. The covalent warhead was highly sensitive to modifications of the sulfone or vinyl substituents. However, numerous alterations to the core 5-membered heterocycle and its aryl substituent were well tolerated and several analogs were identified that enhanced CHIKV nsP2 binding. For example, the 4-cyanopyrazole analog 8d exhibited a kinact /Ki ratio >10,000 M-1s-1. 3-Arylisoxazole was identified an isosteric replacement for the 5-membered heterocycle, which circumvented the intramolecular cyclization that complicated the synthesis of pyrazole-based inhibitors like 1a. The accumulated structure-activity data was used to build a ligand-based model of the enzyme active site, which can be used to guide the design of covalent nsP2 protease inhibitors as potential therapeutics against alphaviruses.

Do 2-(Benzoyl)piperidines Represent a Novel Class of hDAT Reuptake Inhibitors?

2-(Benzoyl)piperidines (analogues of 1a), structural hybrids of the clinically employed ADHD medication methylphenidate (2) and the abused synthetic cathinone pentedrone (3), have been previously reported to act as novel and selective reuptake inhibitors of the human dopamine transporter (hDAT). One of the more potent benzoylpiperidines, as is the case with methylphenidate analogues, is its 3,4-dichloroaryl counterpart. Here, we demonstrate using homology models that these compounds (i.e., benzoylpiperidines and methylphenidate analogues) likely bind in a comparable manner at hDAT. In addition, it is shown here that the 3,4-dichlorobenzoylpiperidine analogue of 1a is more potent than its 3,4-dimethyl counterpart, suggesting that the electronic character of the substituents might play a role in the potency of these hybrids. Furthermore, the 3,4-benz-fused (i.e., naphthyl) benzoylpiperidine analogue acts in the same manner as its corresponding methylphenidate counterpart at hDAT. As with its methylphenidate counterpart, the naphthyl compound also acts, rather uniquely (although with lower potency) relative to other members of the two series, at the human serotonin transporter (hSERT). In conclusion, the benzoylpiperidines represent a novel structural class of hDAT reuptake inhibitors that function in a manner similar to their methylphenidate counterparts.

Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands.

In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta[1,2-c]pyrazole-3-carboxamide 1a and its deaza N-cyclohexyl analogue 1b has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of 1a,b, derivatives 1c–j, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays. Among the derivatives, 1d and 1e resulted in the most potent CB1 receptor ligands (KiCB1 = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB1 antagonist activity for the majority of the new compounds, excluding compound 1e, which showed a CB1 partial agonist behaviour. CB1 antagonist activity of 1b was further confirmed by a mouse gastrointestinal transit assay. Significant activity of the new CB1 antagonists towards food intake was showed by preliminary acute assays, evidencing the potentiality of these new derivatives in the treatment of obesity.

Novel Pyrazolo[3,4-d]pyrimidine Derivatives as Potential Antitumor Agents: Exploratory Synthesis, Preliminary Structure-Activity Relationships, and in Vitro Biological Evaluation

In a cell-based screen of novel anticancer agents, the hit compound 1a which bears a pyrazolo[3,4-d]pyrimidine scaffold exhibited high inhibitory activity against a panel of four different types of tumor cell lines. In particular, the IC50 for A549 cells was 2.24 µM, compared with an IC50 of 9.20 µM for doxorubicin, the positive control. Four synthetic routes of the key intermediate 3 of 1a were explored and 1a was prepared via route D on the gram scale for further research. Two analogs of 1a were synthesized and their preliminary structure-activity relationships were studied. Flow cytometric analysis revealed that compound 1a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. These results suggest that the target compound 1a and its analogs with the pyrazolo[3,4-d]pyrimidine scaffold might potentially constitute a novel class of anticancer agents, which requires further studies.

Synthesis, antiproliferative activities and in vitro biological evaluation of novel benzofuransulfonamide derivatives

In a cell-based screen of novel antiproliferative agents, the hit compound 1a, which bears a benzofuransulfonamide scaffold, exhibited broad-spectrum antiproliferative activities against a panel of tumor cell lines. The promising in vitro antiproliferative activity and structural novelty of 1a prompted us to investigate the synthesis of five analogs of 1a and test their antiproliferative activities. The most potent analogue, 1h, exhibited enhanced antiproliferative activities compared with the parent 1a, and exhibited an IC(50) value against NCI-H460 cells of 4.13 μM compared with 4.52 μM for the positive control cisplatin. Flow cytometric analysis revealed that 1h induces significant levels of apoptosis in NCI-H460 cells in vitro at low micromolar concentrations. These results suggest that 1a and analogs based on its benzofuransulfonamide scaffold may constitute a novel class of antiproliferative agents, which deserve further study.

Adduction of cholesterol 5,6-secosterol aldehyde to membrane-bound myelin basic protein exposes an immunodominant epitope.

Myelin degradation in the central nervous system (CNS) is a clinical hallmark of multiple sclerosis (MS). A reduction in the net positive charge of myelin basic protein (MBP) via deimination of arginine to citrulline has been shown to correlate strongly with disease severity and has been linked to myelin instability and a defect that precedes neurodegeneration and leads to autoimmune attack. Recently, we have shown that lipid-derived aldehydes, such as cholesterol 5,6-secosterols atheronal A (1a) and atheronal B (1b), modulate the misfolding of certain proteins such as apolipoprotein B(100), β-amyloid, α-synuclein, and κ- and λ-antibody light chains in a process involving adduction of the hydrophobic aldehyde to lysine side chains, resulting in a decrease in the net positive charge of the protein. In this study, we show that the presence of either atheronal A (1a) or atheronal B (1b) in large unilamellar vesicles (cyt-LUVs) with the lipid composition found in the cytosolic myelin sheath and bovine MBP (bMBP) leads to an atheronal concentration-dependent increase in the surface exposure of the immunodominant epitope (V86-T98) as determined by antibody binding. Other structural changes in bMBP were also observed; specifically, 1a and 1b induce a decrease in the surface exposure of L36-P50 relative to control cyt-LUVs as measured both by antibody binding and by a reduction in the level of cathepsin D proteolysis of F42 and F43. Structure-activity relationship studies with analogues of 1a and 1b point to the aldehyde moiety of both compounds being critical to their effects on bMBP structure. The atheronals also cause a reduction in the size of the bMBP-cyt-LUV aggregates, as determined by fluorescence microscopy and dynamic light scattering. These results suggest that formation of an imine between inflammatory-derived aldehydes, which effectively reduces the cationic nature of MBP, can lead to structural changes in MBP and a decrease in myelin stability akin to deimination and as such may make a hitherto unknown contribution to the onset and progression of MS.

New 3-Alkylamino-4H-thieno-1,2,4-thiadiazine 1,1-Dioxide Derivatives Activate ATP-Sensitive Potassium Channels of Pancreatic Beta Cells

Compound 1a (NN414) is a potent opener of Kir6.2/SUR1 K(ATP) channels. Compound 1a inhibits insulin release in vitro and in vivo and preserves beta cell function in preclinical animal models suggesting that such a compound could find use in treatment or prevention of type 1 and type 2 diabetes. The crystal structure and a convergent synthesis of 1a are presented together with a range of new analogues of 1a. Several compounds, e.g., 6-chloro-3-(1-methyl-1-phenylethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1h), were found to be potent openers of Kir6.2/SUR1 K(ATP) channels and were able to suppress glucose-stimulated insulin release from rat islets in vitro (EC(50) = 0.04 +/- 0.01 muM) and in vivo after intravenous or peroral administration to hyperinsulinemic obese Zucker rats (ED(50) = 4.0 mg/kg). Structural modifications of this series of K(ATP) channel openers have provided compounds with promising pharmacokinetic properties indicating that brief periods of beta cell rest can be achieved.

Comparative intramolecular dehydrative lactonization of 4-oxocarboxylic acids

Reaction of 3-(p-toluoyl)propanoic acid, 1a (R = H) with refluxing acetic anhydride resulted quantitatively in 2, a β,γ-unsaturated γ-lactone, which was then converted into 3a, an α,βunsaturated lactone by isomerization with triethylamine. The methyl- substituted compound 1b (R = Me), an analogue of 1a, afforded the 2(5H)-furanone 3b directly by heating with Ac2O. Similar reaction of the cycloalkane- containing oxocarboxylic acids (4,5) led in excellent yields to the fused furanones 6 and 7, while treatment of 2-formyl-, 2-acetyl- and 2-(p-toluoyl)benzoic acids (8a-c) with Ac2O gave the 3-acetoxy-1-(3H)-isobenzofuranones, 9a-c.

5‐HT1F

Possible Antimigraine Mechanisms of Action of the 5HT1F Receptor Agonist LY334370This study investigated whether the selective 5HT1F receptor agonist LY334370 has other possible antimigraine mechanisms in addition to the proposed inhibition of dural plasma extravasation. LY334370 (up to 10(−5) M) had no vasoconstrictor effects on human cerebral arteries in vitro. It had no effect (up to 10 mg kg‐1, i.v.) on neurogenic vasodilation of dural blood vessels produced by electrical stimulation of the dura mater in anesthetized rats. Nor had it any effect (at 3 mg kg‐1, i.v.) on the hyperalgesia produced by injection of carrageenan into the paw of conscious rats or on nociceptive reflex responses in the spinalized, decerebrate rabbit (up to 3 mg per kg, i.v.), indicating that it has no general analgesic properties. However, it significantly inhibited activation of second‐order neurons in the trigeminal nucleus caudalis produced by electrical stimulation of the dura mater in anesthetized rats at 3 mg per kg, i.v. These results provide evidence to suggest that LY334370 has a central mechanism of action in blocking the transmission of nociceptive impulses within the trigeminal nucleus caudalis and that this may represent a mechanism through which it has its antimigraine effect.Novel Potent 5‐HT(1F) Receptor Agonists: Structure‐Activity Studies of a Series of Substituted N‐[3‐(1‐methyl‐4‐piperidinyl)‐1H‐pyrrolo[3,2‐b]pyridin‐5‐yl]amidesCompound 1a (LY334370), a selective 5‐HT(1F) receptor agonist (SSOFRA), inhibited dural inflammation in the neurogenic plasma protein extravasation model of migraine and demonstrated clinical efficacy for the acute treatment of migraine. Although 1a was greater than 100‐fold selective over both the 5‐HT(1B) and 5‐HT(1D) receptors, it exhibited appreciable 5‐HT(1A) receptor affinity. Described here is the synthesis and evaluation of a series of pyrrolo[2,3‐c]pyridine and pyrrolo[3,2‐b]pyridine (2a and 3a) as well as pyrrolo[3,2‐d]pyrimidine (4a) analogues of 1a, compounds prepared in an effort to identify SSOFRAs with improved selectivity over other 5‐HT(1) receptor subtypes. The pyrrolo[3,2‐b]pyridine analogue 3a showed high 5‐HT(1F) receptor affinity but offered no improvement in selectivity compared to 1a. However, the C‐5 acetamide derivative, 3b, was greater than 100‐fold selective over the 5‐HT(1A), 5‐HT(1B), and 5‐HT(1D) receptors. SAR studies of this series determined that alkylamides in particular exhibited high selectivity for the 5‐HT(1F) receptor. Replacement at C‐5 with other substituents decreased affinity or selectivity. These SAR studies identified SSOFRAs that demonstrated oral activity in the neurogenic plasma protein extravasation model, a model indicative of antimigraine activity.

11 H-Isoquino[4,3- c]cinnolin-12-ones : novel anticancer agents with potent topoisomerase I-targeting activity and cytotoxicity

Recent studies have identified 2,3-dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)ethyl]-11 H-isoquino[4,3- c]cinnolin-12-one ( 1a) as a novel topoisomerase I-targeting agent with potent cytotoxic activity. The effect of varied substituents at the 11-position of 2,3-dimethoxy-8,9-methylenedioxy-11 H-isoquino[4,3- c]cinnolin-12-ones on topoisomerase I-targeting activity and cytotoxicity was evaluated. Potent TOP1-targeting activity was observed when the 11-position was substituted with either a 2-( N, N-dimethylamino)ethyl, a 2-( N, N-diethylamino)ethyl, a n-butyl, or a 2-(pyrrolidin-1-yl)ethyl group. The addition of a β-methyl group to 1a provided an analogue with dramatically reduced TOP1-targeting activity and cytotoxicity. Analogues of 1a wherein the 2-( N, N-dimethylamino)ethyl group was replaced with a (2-tetrahydrofuranyl)methyl, a 2-(piperidin-1-yl)ethyl, or a 2-(4-methylpiperazin-1-yl)ethyl substituent exhibited decreased activity as TOP1-targeting agents. Replacement of the dimethoxy groups of 1a with hydrogen atoms resulted in an analogue with significantly decreased TOP1-targeting activity and cytotoxicity. Removal of both the vicinal dimethoxyl groups and the methylenedioxy moiety resulted in a complete loss of TOP1-targeting activity. The presence of a 9-nitro substituent in place of the 8,9-methylenedioxy group of 1a resulted in a decrease in relative TOP1-targeting activity and cytotoxicity. Compounds 1a and the 11- n-butyl analogue 1d were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line MDA-MB-435 was used in these assays. At dose levels that approached its maximum tolerated dose, 1a proved to be effective in inhibiting tumor growth in vivo when administered orally or by ip injection.

Novel potent 5-HT(1F) receptor agonists: structure-activity studies of a series of substituted N-[3-(1-methyl-4-piperidinyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]amides.

Compound 1a (LY334370), a selective 5-HT(1F) receptor agonist (SSOFRA), inhibited dural inflammation in the neurogenic plasma protein extravasation model of migraine and demonstrated clinical efficacy for the acute treatment of migraine. Although 1a was greater than 100-fold selective over both the 5-HT(1B) and 5-HT(1D) receptors, it exhibited appreciable 5-HT(1A) receptor affinity. Described here is the synthesis and evaluation of a series of pyrrolo[2,3-c]pyridine and pyrrolo[3,2-b]pyridine (2a and 3a) as well as pyrrolo[3,2-d]pyrimidine (4a) analogues of 1a, compounds prepared in an effort to identify SSOFRAs with improved selectivity over other 5-HT(1) receptor subtypes. The pyrrolo[3,2-b]pyridine analogue 3a showed high 5-HT(1F) receptor affinity but offered no improvement in selectivity compared to 1a. However, the C-5 acetamide derivative, 3b, was greater than 100-fold selective over the 5-HT(1A), 5-HT(1B), and 5-HT(1D) receptors. SAR studies of this series determined that alkylamides in particular exhibited high selectivity for the 5-HT(1F) receptor. Replacement at C-5 with other substituents decreased affinity or selectivity. These SAR studies identified SSOFRAs that demonstrated oral activity in the neurogenic plasma protein extravasation model, a model indicative of antimigraine activity.

Reversible inhibitors of the gastric (H+/K+)-ATPase. 3. 3-substituted-4-(phenylamino)quinolines.

Previously, gastric (H+/K+)-ATPase inhibitors such as 2 have been prepared as analogues of 1a on the presumption that the 3-carbethoxy substituent plays a key role in establishing the orientation of the 4-arylamino group. In this paper we explore further the contribution made to activity by the quinoline 3-substituent. We show that, for compounds bearing such a substituent, only a particular combination of properties provides high activity, both in vitro and as inhibitors of gastric acid secretion in vivo. The ability of the substituent to affect activity by restricting rotation about the Cquin-N bond through a combination of both a pi-electron withdrawal and hydrogen bonding is supported by the current study. However, high activity is only achieved if the effect of this group on the quinoline pK(a) is kept to a minimum. 3-Acyl substituents provide an optimum combination of electronic properties. From this series, compound 17c (SK&F 96067) was shown to be a potent inhibitor of histamine-stimulated gastric acid secretion after oral dosing in the Heidenhain pouch dog and was selected for further development and evaluation in man.

(2-Methylthio-3-Pyridinecarboxylato)-diethyltin and -di-n-butyltin compounds: synthesis, spectroscopic characterization and in vitro antitumour activity. X-ray crystal structure of bis[diethyl(2-methylthio-3-Pyridinecarboxylato)tin] oxide and of diethyltin bis(2-methylthio-3-pyridinecarboxylate)

The X-ray crystal structures of [diethyl(2-methylthio-3-pyridinecarboxylato)tin] oxide (1a) and diethyltin bis(2-methylthio-3-pyridinecarboxylate) (1b) were determined. Compound 1a is a centrosymmetric dimer with two distinct types of carboxylate moieties and tin atoms with trigonal bipyramidal geometries. Compound 1b is monomeric with a six-coordinate tin atom and two equivalent carboxylate groups chelating the tin atom. Compounds 2a and 2b, the di-n-butyl analogues of 1a and 1b, have also been synthesized and characterized spectroscopically. The in vitro activity of compounds 2b and 2a against the human tumour cell line WiDr, a colon carcinoma, is better than that of cis-platin and doxorubicin. They are much less active than doxorubicin against MCF-7, a mammary tumour cell line. Compound 1b is inactive.

Ternary complexes of cis-(NH 3) 2Pt(II) with model nucleobases (1-methylcytosine, 9-methylguanine) and N- and O-bound amino acids (gly, ala)

The formation and properties of isomeric complexes of cis-(NH 3) 2Pt(II) containing the model nucleobase 1-methylcytosine, 1-MeC, and the amino acid glycine, glyH, are reported. Depending on the pH, different protonation states of amino acid and nucleobase are present. In acidic medium, cis-[(NH 3) 2Pt(1-MeC)(H 2O)] 2+ initially forms with glyH cis-[(NH 3) 2Pt(1-MeC)(glyH- O)] 2+ ( 2b) which slowly at pH 2–3 and faster at pH 4–5 converts into cis-[(NH 3) 2Pt(1-MeC)(gly- N)] + ( 1a). 1a is protonated to give the glyH- N species with a p K a ⋍ 2.8 and deprotonated at the NH 2 group of 1-MeC with a p K a ⋍ 12.5–13. Deprotonation of 2b was not detected up to pH 6, at which point conversion 2b → 1a was complete. 1a was prepared and isolated as the nitrate salt via two different routes, starting either from the gly chelate cis-[(NH 3) 2Pt(gly- N,O)] + or from cis-[(NH 3) 2Pt(1-MeC)(H 2O)] 2+. Only the second way led to both O- and N-bound glycine complexes. In the absence of glyH, cis-[(NH 3) 2Pt(1-MeC)(H 2O)] 2+ undergoes a condensation reaction initially to the μ-hydroxo complex cis-[(NH 3) 2Pt(1-MeC)(OH)Pt(1- MeC)(NH 3) 2] 3+ ( 6) and slowly to a bis(1-methylcytosinato) bridged diplatinum(II) complex, cis-[(NH 3) 2Pt(1-MeC −) 2Pt(NH 3) 2] 2+. Analogues of 1a with 9-methylguanine (9-MeGH) instead of 1-MeC as well as mixed 1-MeC, alanine and mixed 9-MeGH, alanine complexes have also been prepared and isolated.

H–D exchange of 1-methylcycloalkenes in dilute acid at elevated temperatures

Specifically deuteriated cycloalkenes 1-trideuteriomethylcyclopentene-2,5,5-d6 (1b), 1-trideuteriomethylcyclohexene-2,6,6-d6(2b), 1-trideuteriomethylcycloheptene-2,7,7-d6 (3b), and 1-trideuteriomethylcyclooctene-2,8,8-d6 (4b) have been prepared from the corresponding protiated substrates 1a, 2a, 3a, and 4a using a modified HTDA exchange method. The perlabelled analogues of 1a and 2a, 5 and 6, have been synthesized by the same method.