The inhibition of p38 MAPK utilising oxalic amides attached to an azaindole scaffold

This patent application from Scios, Inc. builds upon earlier efforts which identified a distinct scaffold as a p38 mitogen-activated protein kinase (MAPK) inhibitor. A seemingly important characteristic of this company’s scaffold is an indole nucleus, which serves as a core to which groups, such as an oxalic amide and piperidine amide, are attached. This application claims compounds incorporating heteroatoms, such as nitrogen, oxygen and sulfur, into the indole nucleus. Thus, azaindoles, with oxalic amides and piperidine amides attached, are prominently featured throughout this application. The compounds are claimed to be anti-inflammatory agents because of their ability to modulate the release of cytokines from inflammatory cells by interven-ing in the stress-activated signal transduction cascade.     

Studies on pyrrolopyrimidines as selective inhibitors of multidrug-resistance-associated protein in multidrug resistance

Multidrug resistance mediated by P-glycoprotein (Pgp) or multidrug-resistance-associated protein (MRP) remains a major obstacle for successful treatment of cancer. Inhibition of Pgp and MRP transport is important for high efficacy of anticancer drugs. While several Pgp inhibitors have entered clinical trials, the development of specific MRP1 inhibitors is still in its infancy. In our screening program, we have identified a pyrrolopyrimidine (4) as a novel and selective MRP1 inhibitor. Subsequent SAR work on the 4-position of the template revealed the phenethylpiperazine side chain as a potent replacement of the benzylthio group of the lead molecule. Introduction of groups at the 2-position seems to have no detrimental effect on activity. Modifications to the nitrile group at the 7-position resulted in the identification of analogues with groups, such as amides, with superior pharmacokinetic profiles. In vivo efficacy has been demonstrated by xenograft studies on selected compounds.     

基于喹喔啉为母核的PI3K抑制剂的合成及抗肿瘤活性研究

以含有喹喔啉母核的PI3K抑制剂XL765和WR23为结构基础,通过生物电子等排,在喹喔啉母核上2位引入取代苯氧基片段,延长3位连接链改为磺酰肼,并在7位引入氟原子;去掉3位取代并在7位引入丙烯酰胺基。初步设计并合成了22个喹喔啉类衍生物,通过1H NMR、13C NMR、ESI-MS进行结构确证。以人非小细胞肺癌A549、人乳腺癌细胞MCF-7、人结肠癌细胞HCT-116和人肝癌细胞HepG2进行体外抗肿瘤活性筛选(MTT法)。结果表明, P6b、P6e、P6f对HCT116活性较好(IC50=3.24, 4.78和4.50μmol·L-1), P6d对MCF-7具有较强抑制作用(IC50=0.228 7μmol·L-1)。     

Synthesis, physicochemical characterization, and biological activities of new carnosine derivatives stable in human serum as potential neuroprotective agents

The synthesis and the physicochemical and biological characterization of a series of carnosine amides bearing on the amido group alkyl substituents endowed with different lipophilicity are described. All synthesized products display carnosine-like properties differentiating from the lead for their high serum stability. They are able to complex Cu(2+) ions at physiological pH with the same stoichiometry as carnosine. The newly synthesized compounds display highly significant copper ion sequestering ability and are capable of protecting LDL from oxidation catalyzed by Cu(2+) ions, the most active compounds being the most hydrophilic ones. All the synthesized amides show quite potent carnosine-like HNE quenching activity; in particular, 7d, the member of the series selected for this kind of study, is able to cross the blood-brain barrier (BBB) and to protect primary mouse hippocampal neurons against HNE-induced death. These products can be considered metabolically stable analogues of carnosine and are worthy of additional investigation as potential neuroprotective agents.     

Novel 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents

A series of novel 3-nitro-1H-1,2,4-triazole-based (and in some cases 2-nitro-1H-imidazole-based) amides and sulfonamides were characterized for their in vitro antitrypanosomal and antileishmanial activities as well as mammalian toxicity. Out of 36 compounds tested, 29 (mostly 3-nitro-1H-1,2,4-triazoles) displayed significant activity against Trypanosoma cruzi intracellular amastigotes (IC(50) ranging from 28 nM to 3.72 μM) without concomitant toxicity to L6 host cells (selectivity 66-2782). Twenty-three of these active compounds were more potent (up to 58-fold) than the reference drug benznidazole, tested in parallel. In addition, nine nitrotriazoles which were moderately active (0.5 μM ≤ IC(50) < 6.0 μM) against Trypanosoma brucei rhodesiense trypomastigotes were 5-31-fold more active against bloodstream-form Trypanosoma brucei brucei trypomastigotes engineered to overexpress reduced nicotinamide adenine dinucleotide dependent nitroreductase. Finally, three nitrotriazoles displayed a moderate activity against the axenic form of Leishmania donovani . Therefore, 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides are potent antitrypanosomal agents.     

Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists

As a potent, specific antagonist for the brain cannabinoid receptor (CB1), the biarylpyrazole N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1) was the lead compound for initiating studies designed to examine the structure-activity relationships of related compounds and to search for more selective and potent cannabimimetic ligands. A series of pyrazole derivatives was designed and synthesized to aid in the characterization of the cannabinoid receptor binding sites and also to serve as potentially useful pharmacological probes. Therapeutically, such compounds may have the ability to antagonize harmful side effects of cannabinoids and cannabimimetic agents. Structural requirements for potent and selective brain cannabinoid CB1 receptor antagonistic activity included (a) a para-substituted phenyl ring at the 5-position, (b) a carboxamido group at the 3-position, and (c) a 2,4-dichlorophenyl substituent at the 1-position of the pyrazole ring. The most potent compound of this series contained a p-iodophenyl group at the 5-position, a piperidinyl carboxamide at the 3-position, and a 2,4-dichlorophenyl group at the 1-position of the pyrazole ring. The iodinated nature of this compound offers additional utility as a gamma-enriching SPECT (single photon emission computed tomography) ligand that may be useful in characterizing brain CB1 receptor binding in vivo.     

Novel selective PDE4 inhibitors. 3. In vivo antiinflammatory activity of a new series of N-substituted cis-tetra- and cis-hexahydrophthalazinones

The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC(50) = 8.6-9.4). The N-cycloheptyl- and N-adamantanyltetrahydrophthalazinones (7h, 8, 10, 11) show high in vivo antiinflammatory activities after oral application. Additionally, some phthalazinones were found to exhibit potent suppression of LPS-induced TNFalpha release and show moderate potency against fMLP-stimulated production of ROS.     

Immunotropic properties of 2-aminobenzimidazole derivatives in cultures of human peripheral blood cells, Part 5

The reaction of 2-aminobenzimidazole with selected 4-methoxy-,2,4-dimethoxy-, 4-chloro-, 4-nitro-, and 2-nitrocinnamic acid under different conditions has been described. Two series of derivatives were obtained: 4-aryl-1,2,3,4-tetrahydropyrimido[1,2-a]-benzimidazol-2-ones (1-3) or substituted amides 4, 5, 7. The following compounds: 4-(p-methoxyphenyl)- (1), 4-(2,4-dimethoxyphenyl)- (2), 4-(p-chlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazo l-2-one (3), amides: 2-(p-nitrocinnamoylamino)- (4), 2-(p-methoxycinnamoylamino)-benzimidazole (5), and 3-methyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-2-one (6), recently synthesized, have been selected for further studies. Among the studied compounds, 3 and 4 strongly inhibited PHA-induced proliferation of human lymphocytes and weaker, but significantly, MLC-induced lymphocyte proliferation. 3 and 4 inhibited also LPS- or MLC-induced TNF-alpha production. In addition, TNF-alpha production, induced by LPS, was inhibited by compounds 1 and 2. Higher activity of 3 and 4 could be associated with the presence in their structures of -Cl and -NO2 substituents as compared with compounds possessing -OCH3 groups. Compounds 3 and 4 were not toxic when administered orally to mice which predisposes them for further investigations with a chance of clinical application.     

Vertex inhibitors of Aurora-2, glycogen synthase kinase-3 and Src kinase

Four patent applications from Vertex have recently been published relating to inhibitors of protein kinases. The compounds described in this invention are claimed as inhibitors of Aurora-2, glycogen synthase kinase-3 (GSK-3), and Src protein kinases. The applications are highly homologous, in that an identical set of five core templates are described as especially preferred in each of the four applications. The compounds are differentiated from one another by the substituent off of the 4-amino position of the core template. A series of 30 – 40 representative compounds are provided for each application but none are described as especially preferred and no biological data are provided for any of these representative compounds. These recent publications signal a continued interest by Vertex in pan-inhibitors of Aurora-2, GSK-3 and Src.     

Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 3. Pyridinylalkyl-substituted 8-[(arylsulfonyl)amino]octanoic acids.

A series of 8-[(arylsulfonyl)amino]octanoic acids substituted with a pyridinylalkyl group along the chain were synthesized and tested in vitro for their ability to both antagonize the binding of thromboxane A2 to its receptors and to inhibit the thromboxane synthase enzyme. This series of compounds were found to inhibit the U 46619-induced aggregation of human platelets and the U 46619-induced contraction of dog saphenous vein. The compounds also inhibited TxA2 biosynthesis in a human microsomal platelet preparation. The relative position of the pyridinylalkyl and arylsulfonamide groups had significant effects on the thromboxane receptor antagonist (TxRA) activity and thromboxane synthase inhibitor (TxSI) activity. Compounds with the pyridine ring at the 7- or 8-position of the octanoic acid side chain were weakly active as TxSI but behaved as potent TxRA at the platelet receptor for TxA2. However, these compounds were agonists at the vascular receptor. Substitution of the pyridinylalkyl group at the 2- or 3-position resulted in compounds with potent TxSI activity and weak TxRA activity. The activity profile of the compounds with the pyridinylalkyl substitution at the 4-, 5-, or 6-position was very desirable. Compound 22 with a pyridinylpropyl substituent at the 4-position was found to display extremely potent TxRA and TxSI properties.     

Synthesis and evaluation of cyclic secondary amine substituted phenyl and benzyl nitrofuranyl amides as novel antituberculosis agents

In an ongoing effort to develop new and potent antituberculosis agents, a second-generation series of nitrofuranyl amides was synthesized on the basis of the lead compound 5-nitrofuran-2-carboxylic acid 3,4-dimethoxybenzylamide. The primary design consideration was to improve the solubility and consequently the bioavailability of the series by the addition of hydrophilic rings to the benzyl and phenyl B ring core. The synthesis of 27 cyclic, secondary amine substituted phenyl and benzyl nitrofuranyl amides is described and their activity against Mycobacterium tuberculosis reported. The series showed a strong structure-activity relationship as the benzyl nitrofuranyl amides were significantly more active than similarly substituted phenyl nitrofuranyl amides. Para-substituted benzyl piperazines showed the most antituberculosis activity. Compounds in the series were subsequently selected for bioavailability and in vivo testing. This study led to the successful discovery of novel compounds with increased antituberculosis activity in vitro and a better understanding of the requisite pharmacological properties to advance this class.     

Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-one (TIBO) derivatives

A series of 6-substituted 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-ones (9) have been synthesized and tested for their ability to inhibit the replication of the HIV-1 virus in MT-4 cells. Two synthetic methods are described, one of which allows the synthesis of single enantiomers of the final products. A structure-activity study was done within the series of compounds to determine the optimum group for the 6-position substitution and to determine whether the activity was enantiospecific at the 5-position, which was substituted with a methyl group. The best analogue, 9jj, inhibited HIV-1 with an IC50 of 4 microM, which is comparable to the activity level of DDI, a 2',3'-dideoxynucleoside-type structure undergoing clinical trials as an anti-AIDS therapy.     

Novel 3,3a,4,5,6,7-hexahydroindazole and arylthiazolylpyrazoline derivatives as anti-inflammatory agents

A novel series of 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole substituted at the 2-position were synthesized. The reaction of 2, 6-bis-benzylidenecyclohexanone (1) with thiosemicarbazide in the presence of NaOH afforded a mixture of the 3-H, 3a-H trans 2 and cis 2a diastereoisomers which have been separated by fractional recrystallization. Interaction of the first intermediate 2 with substituted phenacyl bromides, aromatic aldehydes and chloroacetic acid in presence of a mixture of acetic acid and acetic anhydride, and 2, 3-dichloroquinoxaline yielded the corresponding 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole derivatives substituted at the 2-position with 4-aryl-2-thiazolyl 3a, b, 5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl 4a, b and thiazolo[4, 5-b]quinoxalin-2-yl 5, respectively. Moreover, the other intermediates 3, 5-diaryl-1-thiocarbamoyl-2-pyrazolines 7a-d were reacted with the previously-mentioned reagents and gave the corresponding 3, 5-diaryl-1-(4-aryl-2-thiazolyl)-2-pyrazolines 8a-h, 3, 5-diaryl-1-(5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl)-2-pyrazolines 9a-d and 3, 5-diaryl-1-(thiazolo[4, 5-b]quinoxalin-2-yl)-2-pyrazoline derivatives 10a, b, respectively. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity. The structures of the new compounds were confirmed by elemental analyses as well as (1)H-NMR, IR, and MS data.     

Studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones

The synthesis of a series of 5-[4-(pyridylalkoxy)benzyl]-2, 4-thiazolidinediones is described. These compounds were evaluated for hypoglycemic and hypolipidemic activities in genetically obese and diabetic mice, yellow KK. 2-(2-Pyridyl)alkoxy derivatives were found to have much better hypoglycemic and hypolipidemic activities than 2-(3-pyridyl)- and 2-(4-pyridyl)alkoxy derivatives or even the previously reported compound, ciglitazone. The introduction of a hydroxyl group at the 2-position of the ethoxy chain potentiated the activities. Among the potent compounds, pioglitazone (AD-4833) was selected as a candidate compound.     

3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT(2A) receptor antagonists

The development of very high affinity, selective, and bioavailable h5-HT(2A) receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT(2A) receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT(2A) receptors, with bioavailability of 80% and half-life of 12 h in rats.     

Contraceptive agents from cycloaddition reactions of diarylcyclopropenones and diarylthiirene 1, 1-dioxides.

The potential for compounds with antifertility activity from the reactions of diphenylcyclopropernone (1) and 2, 3-diphenylthiirene 1, 1-dioxide (2) with enamines is described. In certain instances, a marked dissociation of antifertility from estrogenic activity was possible. Two series were studied extensively, one was stilbene amides (7) and the other stilbene amino ketones (8). The latter series (8) afforded several materials from which, on further biological work-up, was singled out compound 21 as a potent antifertility agent in rats and hamsters.     

Synthesis and activity of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines in animal models of epilepsy

A series of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines derivatives was synthesized and evaluated for anticonvulsant activity. The compounds were screened in mice for their ability to antagonize maximal electroshock- and bicuculline-induced seizures; neurotoxicity was evaluated in the rotorod test. The anticonvulsant activity of the most potent compounds in this series was also examined in kindled amygdaloid rats and in photoepileptic Papio papio baboons. Phenobarbital, diphenylhydantoin, carbamazepine, and sodium valproate were used as standard antiepileptic drugs. The structure-activity relationships in this series were examined by either varying the aryl ring in the 6-position of the pyridazine ring or by modifying the 3-amino side chain. Only the compounds with a phenyl ring in the 6-position of the pyridazine ring exhibited appreciable anticonvulsant activity. Furthermore, a 4-hydroxypiperidine side chain in the 3-position of the pyridazine ring appeared essential for anticonvulsant activity. Substituting the phenyl ring with a Cl in the 2-position led to a substantial increase of activity; disubstituting the phenyl ring with a Cl in the 2- and 4-positions yielded the most potent compounds in this series, some of which were as potent or more potent than phenobarbital. Two compounds, 6-(2-chlorophenyl)-3-(4-hydroxypiperidino)pyridazine (2) and 6-(2,4-dichlorophenyl)-3-(4-hydroxypiperidino)pyridazine (3), were selected for further studies. Clinical evaluation of these compounds is in progress.     

New broad-spectrum cephalosporins with anti-pseudomonal activity. I. Synthesis and antibacterial activity of 7 beta-[D-2-[(4-hydroxy-1,5-naphthyridine-3-carbonylamino)- and (4-hydroxypyridine-3-carbonylamino)]-2-(4-hydoxyphenyl)acetamido] cephalosporins

The synthesis and the antibacterial activity of 7 beta-[D-2-[(4-hydroxy-1,5-naphthyridine-3-carbonylamino)- and (4-hydroxypyridine-3-carbonylamino)]-2-(4-hydroxyphenyl)acetamido]-cephalosporins with various substituents at the 3-position in the cephem nucleus are described. These compounds exhibited strong antibacterial activities against a variety of Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa and Enterobacter aerogenes, which are insensitive to cefazolin and cefmetazole. The compounds (3e, 4e) having a 1-methyl-1H-tetrazolylthiomethyl group at the 3-position appeared to show the best activity in each series. The 4-hydroxypyridine-3-carbonylamino derivative 4e gave higher peak serum concentrations and urinary recovery rates than those of the 4-hydroxy-1,5-naphthyridine derivative 3e when administered subcutaneously to mice and intramuscularly to rats.     

BMS-232632 (Novartis/Bristol-Myers Squibb)

BMS-232632, an azapeptide HIV protease inhibitor, is in development by Bristol-Myers Squibb (BMS), under license from Novartis, as a potential treatment for HIV/AIDS [248556]. Early preclinical work was carried out by Novartis [248556]. BMS-232632 was developed as part of a series of compounds (as CGP-73547) and evaluated against drug-resistant strains of HIV; the compounds in this series belong to a series of azadipeptide analogs and are bis(L-tert-leucine) derivatives that exhibit good antiviral activity and satisfactory pharmacokinetic profiles [297907]. Novartis subsequently discontinued evaluation of the compound in November 1999 [347827]. Phase II trials had already begun by July 1999 [334335] and BMS expects NDA filing to take place in 2001 [358937]. Use of BMS-232632 in combination with other antiretroviral agents has demonstrated that it may be used in combination with a variety of nucleoside analogs and protease inhibitors [298464]. It is thought to have a genotypic resistance profile that differs from that of other protease inhibitors [302157]. In February 1999, Lehman Brothers predicted the drug had a 30% probability of reaching market, with an estimated first launch date in 2001. The analysts predicted peak sales would occur in 2007, with sales of $500 million in the US and $300 million in the rest of the world at that time [319225].     

Synthesis of 2-(4-biphenylyl)quinoline-4-carboxylate and carboxamide analogs. New human neurokinin-3 (hNK-3) receptor antagonists

The 2-phenylquinoline-4-carboxamide 1 (Chart[TH]1) has been found to possess moderate affinity for human neurokinin-3 (hNK-3) receptor. In the present work, and in a trial to investigate the effect of the lipophilic moiety at C-2 of the quinoline ring on the antagonistic activity, an enlargement of the aromatic area at this position was suggested. In this respect, two series of 2-(4-biphenylyl)quinoline-4-carboxylates and carboxamides have been synthesized with certain modifications at the quinoline-2 and 4-position in order to study their effect on the anticipated hNK-3 receptor antagonistic activity. Fifteen compounds were screened for such activity using guinea-pig isolated ileum longitudinal muscle preparation and senktide as selective hNK-3 receptor agonist. Some compounds showed considerable antagonistic effect. Compound 7b, 6-bromo-2-(4-biphenylyl)quinoline-4-carboxylic acid, was the most prominent hNK-3 receptor antagonist in this study. Unexpectedly, some compounds were agonists.