Antiallergy agents. 1. Substituted 1,8-naphthyridin-2(1H)-ones as inhibitors of SRS-A release

A novel class of antiallergy agents, the substituted 1,8-naphthyridin-2(1H)-ones, is described. The present compounds are orally active, potent inhibitors of allergic and nonallergic bronchospasm in animal models. Structure-activity studies of the lead compound in this series, 1-phenyl-3-n-butyl-4-hydroxynaphthyridin-2(1H)-one (11), identified three compounds of interest, 1-phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one (12), 1-(3'-chlorophenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H )-one (87), and 1-(3'-methoxyphenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1 H)-one (89). The mechanism of antiallergy activity may involve inhibition of the release of the sulfidopeptide leukotrienes. 1-Phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one, Sch 33303 (12), was selected for preclinical development as an antiallergy agent.     

Synthesis and structure-activity relationships of 7-substituted 3-(2, 6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones as selective inhibitors of pp60(c-src)

7-substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones are potent inhibitors of protein tyrosine kinases, with some selectivity for c-Src. The compounds were prepared by condensing 4, 6-diaminonicotinaldehyde with 2,6-dichlorophenylacetonitrile and selectively converting the 2- and 7-amino groups of the product to hydroxy and fluoro groups, respectively, by prolonged diazotization in 50% aqueous fluoboric acid. N-Methylation, followed by treatment with aliphatic diamines, aromatic amines, or their derived lithium anions, gave the desired compounds. Selected isomeric 1, 8-naphthyridin-2(1H)-ones were also prepared in order to evaluate the relative contributions of both ring A aza atoms of the related pyrido[2,3-d]pyrimidin-7(8H)-ones to the inhibitory activity. The compounds were evaluated for their ability to prevent phosphorylation of a model substrate by c-Src, FGF-1 receptor, and PDGF-beta receptor enzymes. Overall, there was a high degree of correlation of the activities against the different kinases, with c-Src being generally the most sensitive to structural changes. 1, 6-Naphthyridin-2(1H)-one analogues bearing basic aliphatic side chains [7-NH(CH(2))(n)()NRR, 7-NHPhO(CH(2))(n)()NRR, or 7-NHPhN(CH(2))(4)NMe] were the most potent against c-Src (IC(50)s of 10-80 nM), showing good selectivity with respect to PDGFR (10-300-fold) but less with respect to FGFR. The 1, 6-naphthyridin-2(1H)-ones showed broadly similar activity to the analogous pyrido[2,3-d]pyrimidin-7(8H)-ones, whereas the 1, 8-naphthyridin-2(1H)-ones were at least 10(3)-fold less potent. These results, indicating that the 3-aza atom in the pyrido[2, 3-d]pyrimidin-7(8H)-ones is mandatory, whereas the 1-aza atom is not, support the published binding model for these compounds to c-Src (J. Med. Chem. 1998, 41, 1752), where the 3-aza and 2-NH atoms form a bidentate H-bond donor-acceptor motif that interacts with Met341 and the 1-aza atom is not involved in specific binding interactions.     

3,4-Dihydroquinolin-2(1H)-ones as combined inhibitors of thromboxane A2 synthase and cAMP phosphodiesterase.

A series of 1H-imidazol-1-yl- and 3-pyridyl-substituted 3,4-dihydroquinolin-2(1H)-ones was designed and synthesized as combined inhibitors of thromboxane (TXA2) synthase and cAMP phosphodiesterase (PDE) in human blood platelets. A number of structures, e.g. 4b, 7a, 7e, 13a, and 21-25, were superior to dazoxiben 26 as inhibitors of TXA2 synthase in in vitro ADP-induced aggregation experiments with human blood platelets. The TXA2 synthase inhibitory activity was confirmed by measurement of the prostanoid metabolites derived from 14C-labeled arachidonic acid. Three compounds (7a, 7e, and 25) demonstrated in vitro inhibition of human platelet cAMP PDE at micromolar concentrations in conjunction with their TXA2 synthase inhibitory activity. Synergistic enhancement of antiaggregatory and antithrombotic actions was expected when simultaneous stimulation of adenylate cyclase (through increased PGI2 production) and inhibition of platelet cAMP PDE were possible from the same compound. Ex vivo and in vivo experiments were conducted in rats and mice, respectively, to evaluate the effects of compounds 7e and 23 on platelet aggregation and thrombotic events within these animals. Compound 7e, which has a comparable level of TXA2 synthase (IC50 1.2 microM) and human platelet cAMP PDE (IC50 6.4 microM) inhibitory activities, was found to be orally bioavailable with a long duration of action and offered effective protection against mortality in a collagen-epinephrine-induced pulmonary thromboembolism model in mice. Significant blood pressure and heart rate effects were observed for several compounds, e.g. 7e, 9e, 13a, 13d, 18, 20, 21, and 23, when dosed orally in conscious spontaneously hypertensive rats.     

Conformationally restrained fentanyl analogues. 2. Synthesis and analgetic evaluation of perhydro-1,6-naphthyridin-2-ones

Conformational flexibility of the N-acyl portion of fentanyl-type analgetics was restricted through the synthesis of novel perhydro-1,6-naphthyridin-2-one derivatives. Neither the cis-fused derivative (5a), the trans-fused derivative(5b), nor the enamide 8a possessed analgetic activity in the mouse tail-flick assay, reaffirming the sensitivity of this portion of 4-anilidopiperidine analgetics to conformational restraint.     

Novel selective PDE4 inhibitors. 1. Synthesis, structure-activity relationships, and molecular modeling of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones and analogues

A number of 6-(3,4-dimethoxyphenyl)-4,5-dihydro-2H-pyridazin-3-ones and a novel series of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones were prepared and tested on the cGMP-inhibited phosphodiesterase (PDE3) and cAMP-specific phosphodiesterase (PDE4) enzymes. All tested compounds were found to specifically inhibit PDE4 except for pyridazinone 3b, which showed moderate PDE4 (pIC(50) = 6.5) as well as PDE3 (pIC(50) = 6.6) inhibitory activity. In both the pyridazinone and phthlazinone series it was found that N-substitution is beneficial for PDE4 inhibition, whereas in the pyridazinone series it also accounts for PDE4 selectivity. In the phthalazinone series, the cis-4a,5,6,7,8,8a-hexahydrophthalazinones and their corresponding 4a,5,8,8a-tetrahydro analogues showed potent PDE4 inhibitory potency (10/11c,d: pIC(50) = 7.6-8.4). A molecular modeling study revealed that the cis-fused cyclohexa(e)ne rings occupy a region in space different from that occupied by the other fused (un)saturated hydrocarbon rings applied; we therefore assume that the steric interactions of these rings with the binding site play an important role in enzyme inhibition.     

Potent and selective mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors. 1. 4-(4-bromo-2-fluorophenylamino)-1- methylpyridin-2(1H)-ones

The role of MEK 1,2 in cancer tumorgenesis has been clearly demonstrated preclinically, and two selective inhibitors are currently undergoing clinical evaluation to determine their role in the human disease. We have discovered 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones as a new class of ATP noncompetitive MEK inhibitors. These inhibitors exhibit excellent cellular potency and good pharmacokinetic properties and have demonstrated the ability to inhibit ERK phosphorylation in HT-29 tumors from mouse xenograft studies.     

Synthesis and central nervous system effects of 8.9-dihydro(1)benzazepino(3,2.1-ak)(1,4)benzodiazepin-1(2H)-ones and (1) binzazepino(3,2,1-jk)(1,4)benzodiazepin-1(2H)-ones.

A series of 4-alkyl-8,9-dihydro[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives was synthesized. Two approaches for the synthesis of 4-alkyl[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives are described. All compounds were evaluated for CNS activity. None showed significant activity. The results obtained indicate that in the case of the 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one a phenyl group at the 1 position causes a fall in CNS activity not only when it is free but also when fused to the benzodiazepine system.     

Thromboxane synthetase inhibitors and antihypertensive agents. 4. N-[(1H-imidazol-1-yl)alkyl] derivatives of quinazoline-2,4(1H,3H)-diones, quinazolin-4(3H)-ones, and 1,2,3-benzotriazin-4(3H)-ones

The quinazolinedione, quinazolinone, and 1,2,3-benzotriazinone title compounds were prepared as analogues of N-[(1H-imidazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-diones which were the subject of a previous report from our laboratories. These compounds were evaluated as thromboxane (TX) synthetase inhibitors and as antihypertensive agents. While each series of compounds had activity both as TX synthetase inhibitors and as antihypertensives, the best compounds were N-[(1H-imidazol-1-yl)alkyl]quinazoline-2,4(1H,3H]-diones (V). In general these compounds were all selective enzyme inhibitors at least equipotent with the standard dazoxiben. These compounds were also very active antihypertensive agents as determined in SHR. The SAR is discussed for both types of activity. Compound 20a was further evaluated for TX formation inhibiting properties in several other platelet types both in vitro and ex vivo and is between 100 and 1000 times more potent than dazoxiben.     

Novel 3-hydroxy-2(1H)-pyridinones. Synthesis, iron(III)-chelating properties, and biological activity

The synthesis of a range of novel bidentate and hexadentate ligands containing the chelating moiety 3-hydroxy-2(1H)-pyridinone is described. The pKa values of the ligands and the stability constants of their iron(III) complexes have been determined. The stability constant of the iron(III) complex of one of the hexadentate ligands is comparable to that of desferrioxamine B. The distribution coefficients of the ligands and their iron(III) complexes were also determined. One of the novel hexadentate compounds has been shown to markedly enhance iron(III) excretion from both hepatocytes and iron-overloaded mice.     

吡啶酮类HIV-1非核苷逆转录酶抑制剂:组合优化设计策略（英文）

随着艾滋病病毒在全球范围内的迅速传播和耐药性的日益严重,开发新型有效的抗艾滋病药物显得尤为迫切。非核苷逆转录酶抑制剂(NNRTIs)以其结构多样性、独特的作用机制、高效低毒等特点,成为对抗HIV感染最重要的抗逆转录病毒药物之一。吡啶酮衍生物作为NNRTIs的一种,在近几十年的研究中取得了令人瞩目的成果。在这篇综述中,我们概述了当前药物设计和药物化学方面的研究,为发展下一代吡啶酮类HIV-1 NNRTIs提供思路。     

Pharmacologic activity of 1-lupinylquinoxalin-2(1H)-ones, 3,6-disubstituted

Five 1-lupinyl-3R'-6R"-quinoxalin-2(1H)-ones were tested in mice for acute toxicity, explorative activity inhibition, analgesic activity and for antagonism against physostigmine, strychnine and pentylentetrazol (cardiazol). As reference compounds were used chloropromazine, morphine, atropine and diazepam respectively. All tested compounds inhibit the explorative activity and exhibit high analgesic activity. Compound (I) protects completely the animals from physostigmine toxicity, while compound (IV) antagonizes, although only slightly, all the toxicants tested.     

Syntheses of Novel 3-Amino-2(1H)-thioxo-4(3H)-quinazolinones and Evaluation of Their Immunotropic Activity. Part III

The synthesis of two series of derivatives containing the quinazolinone-4 moiety is described. 3-Amino-2(1H)-thioxo-4(3H)-quinazolinone ( 1 ) was subjected to reactions with halogenoketones and halogenoaldehydes, leading to the production of the corresponding ketones, aldehydes, Schiff bases, and 6-oxo-1,4,5-thiadiazin[2,3-b]quinazoline derivatives. Subsequently, 1 was condensed with selected α,β-unsaturated carbonyl compounds, aldehydes, ketones, acid chlorides, and esters. The compounds were tested for their potential activity in a model of humoral and cellular immune response. The tests showed that the compounds exhibited differential immunotropic activities. Of particular interest is compound 19 , exhibiting a strong stimulatory activity with regard to cellular immune response and compound 16 exerting a strong inhibitory action in both types of the immune response.     

Pyrazolidine-3,5-diones and 5-hydroxy-1H-pyrazol-3(2H)-ones, inhibitors of UDP-N-acetylenolpyruvyl glucosamine reductase

A series of pyrazolidine-3,5-dione and 5-hydroxy-1H-pyrazol-3(2H)-one inhibitors of Escherichia coli UDP-N-acetylenolpyruvyl glucosamine reductase (MurB) has been prepared. The 5-hydroxy-1H-pyrazol-3(2H)-ones show low micromolar IC(50) values versus E. coli MurB and submicromolar minimal inhibitory concentrations (MIC) against Staphylococcus aureus GC 1131, Enterococcus faecalis GC 2242, Streptococcus pneumoniae GC 1894, and E. coli GC 4560 imp, a strain with increased outer membrane permeability. None of these compounds show antimicrobial activity against Candida albicans, a marker of eukaryotic toxicity. Moreover, these compounds inhibit peptidoglycan biosynthesis, as assessed by measuring the amount of soluble peptidoglycan produced by Streptococcus epidermidis upon incubation with compounds. A partial least squares projection to latent structures analysis shows that improving MurB potency and MIC values correlate with increasing lipophilicity of the C-4 substituent of the 5-hydroxy-1H-pyrazol-3(2H)-one core. Docking studies using FLO and PharmDock produced several binding orientations for these molecules in the MurB active site.     

Novel selective phosphodiesterase (PDE4) inhibitors. 4. Resolution,absolute configuration,and PDE4 inhibitory activity of cis-tetra- and cis-hexahydrophthalazinones

Recently, we reported that 4-catechol-substituted cis-(+/-)-4a,5,6,7,8,8a-hexa- and cis-(+/-)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones show potent inhibition of phosphodiesterase (PDE4) activity, while the corresponding trans racemic mixtures exhibit only weak to moderate activity. To determine the absolute configuration and PDE4 inhibitory activity of the individual cis-enantiomers, several optically active phthalazinones have been synthesized. The enantiomers of the various gamma-keto acids, used as starting materials, were resolved in a classical way by the formation of diastereomeric salts, and each was converted to optically active phthalazinone in an enantioselective manner. The absolute configuration of the (+)-enantiomer of cis-hexahydrophthalazinone (+)-12 was determined by X-ray crystallography. The carbon atoms at the 4a and 8a positions were found to have the S- and R-configuration, respectively. In the present series of hexa- and tetrahydrophthalazinones, stereoselectivity for PDE4 inhibition is observed; the cis-(+)-enantiomers of the phthalazinones display high inhibitory activity, whereas their (-)-counterparts exhibit only weak to moderate activity. It is likely that all cis-(+)-phthalazinones have a (4aS,8aR)-configuration and vice versa for the cis-(-)-analogues. In the current series, the N-adamantan-2-yl analogue (+)-14 shows the most potent inhibition of PDE4 (pIC(50) = 9.3); the corresponding (-)-enantiomer is 250-fold less active. In addition, the N-substituted tetrahydrophthalazinones under study were investigated for their in vivo antiinflammatory activities by examining the suppression of arachidonic acid (AA) induced mouse ear edema formation. In this assay analogues (+)-14 and (+)-15 were found to be potent antiinflammatory agents showing about 50% inhibition at 30 micromol/kg po.