Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally-active calcium-sensing receptor antagonists

Synthesis and structure–activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.     

Cerebroprotective effects of angiotensin II (AT 1) receptor antagonists?

The results of the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study show that treatment with an angiotensin receptor blocker (ARB) in the acute phase of a stroke improves mortality and cardiovascular morbidity. In addition, direct comparative antihypertensive trials have demonstrated beneficial effects of ARBs in preventing stroke. These possible cerebro-protective effects of ARBs are supported by animal studies, demonstrating that stimulation of the AT2 receptor was related to a reduction in both cerebral infarct size and mortality. In the present report, we review both pathophysiological and clinical evidence for possible cerebroprotective effects of ARBs, independent of their effect on blood pressure.     

Development of 2-aryl substituted quinazolin-4(3H)-one,pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E2 synthase-1 inhibitors

mPGES-1 is inducible terminal synthase acting downstream of COX enzymes in arachidonic acid pathway, regulates the biosynthesis of pro-inflammatory prostaglandin PGE₂. Cardiovascular side effect of coxibs and NSAIDs, selective for COX-2 inhibition, stimulated interest in mPGES-1, a therapeutic target with potential to deliver safe and effective anti-inflammatory drugs. The synthesis and structure activity relationship of a series of compounds from 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds as mPGES-1 inhibitor are discussed. A set of analogs (28, 48, 49) were identified with <10 nM potencies in the recombinant human mPGES-1 enzyme and in the A549 cellular assays. These analogs were also found to be potent in the human whole blood assay (<400 nM). Furthermore, the representative compound 48 was shown to be selective with other prostanoid synthases and was able to effectively regulate PGE₂ biosynthesis in clinically relevant inflammatory settings, in comparison with celecoxib.     

Synthesis and antimicrobial activity of polyhalobenzonitrile quinazolin-4(3H)-one derivatives

A novel series of polyhalobenzonitrile quinazolin-4(3H)-one derivatives were synthesized and characterized by NMR, IR, MS, and HRMS spectra. All of the newly prepared compounds were screened for antimicrobial activities against four strains of bacteria (Gram-positive bacterial: Staphylococcus aureus and Bacillus cereus; Gram-negative bacterial: Escherichia coli and Pseudomonas aeruginosa) and one strain of fungi (Candida albicans). Among the synthesized compounds, 5-(dimethylamino)-8-(2,4,5-trichloro-isophthalonitrile) quinazolin-4(3H)-one (7k) exhibited significant activity towards Gram-positive bacterial, Gram-negative bacterial, and the fungi strains. The MIC (0.8–3.3 μg/mL) and MBC (2.6–7.8 μg/mL) for this compound were close to those of nofloxacin, chlorothalonil, and fluconazole, making it the most potent antimicrobial agents in the series.     

4-arylphthalazin-1(2H)-one derivatives as potent antagonists of the melanin concentrating hormone receptor 1 (MCH-R1)

A novel series of 4-arylphthalazin-1(2H)-one linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of an extensive SAR study probing the effects of substituents on the 4-arylphthalazin-1(2H)-one C-4 aryl group led to the identification of the 4-(3,4-difluorophenyl) derivative as a highly potent MCH-R1 inhibitor with an IC(50)=1nM. However, further investigations showed that this substance has unacceptable pharmacokinetic properties including a high clearance and volume of distribution.     

Synthesis and biological activity of 2-alkylbenzimidazoles bearing a N-phenylpyrrole moiety as novel angiotensin II AT1 receptor antagonists

A series of 2-alkylbenzimidazoles bearing a N-phenylpyrrole moiety were synthesized and evaluated as a novel class of AT(1) receptor antagonists. Among them, compounds 10a and 10g inhibited [(125)I] AngII-binding affinity to AT(1) receptor at nanomolar level and potently inhibited the Ang II-induced pressor response by oral administration. Moreover, evaluation in spontaneously hypertensive rats showed that 10a is an orally active AT(1) receptor antagonist.     

Synthesis and structure-activity relationship of 3-phenyl-3H-quinazolin-4-one derivatives as CXCR3 chemokine receptor antagonists

A series of 3-phenyl-3H-quinazolin-4-ones have been synthesized and tested for affinity and activity at the chemokine CXCR3 receptor. The most potent compound (1d) has been evaluated using radioligand binding and calcium mobilization assays and is considered a useful tool for further characterization of the CXCR3 receptor.     

Discovery of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors

Herein, we report the discovery of a series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors. Structure-activity relationship studies of these compounds led to the identification of the most potent compound, 3-(3-methoxybenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (8k), which showed IC₅₀ values of 0.004 μM and 0.001 μM against ROCK Ⅰ and ROCK Ⅱ, respectively. In vitro, 8k significantly reduced the phosphorylation level of ROCK downstream signaling protein and induce changes in cell morphology and migration. Overall, this study provides a promising lead compound for drug discovery targeting ROCKs.     

Thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDK1 inhibitors discovered by fragment-based screening

Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity against PDK1 in a biochemical enzyme assay.     

Synthesis and biological activity of 1-phenylsulfonyl-4-phenylsulfonylaminopyrrolidine derivatives as thromboxane a(2) receptor antagonists

The synthesis and biological activity of novel 1-phenylsulfonyl-4- phenylsulfonylaminopyrrolidine analogues are described. All compounds were produced through modification of the substituent formally corresponding to the 1,3-dioxane ring system and the omega-octenol side chain of thromboxane A(2) (TXA(2)), in reference to the structure of Daltroban. Several compounds were found to be potent TXA(2) receptor antagonists. Compound 51a was the most effective inhibitor of 9,11-epoxymethano PGH(2) (U-46619)-induced rat aortic strip contraction (IC(50)=0.48 nM).     

3-Aryl-4-hydroxyquinolin-2(1H)-one derivatives as type I fatty acid synthase inhibitors

A series of 3-aryl-4-hydroxyquinolin-2(1H)-ones with fatty acid synthase inhibitory activity was prepared. Starting from a derivative with an IC(50) = 1.4 microM, SAR studies led to compounds with more than 70-fold increase in potency (IC(50) < 20 nM).     

Synthesis of 4-substituted pyrido[2,3-d]pyrimidin-4(1H)-one as analgesic and anti-inflammatory agents

4-Substituted-pyrido[2,3-d]pyrimidin-4(1H)-ones 4a–c were synthesized by oxidation of 4-substituted-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones 3a–c which were in turn prepared from arylidenemalononitriles 1a–c and 6-aminothiouracil 2. The reactivity of compounds 4a–c towards some reagents such as formamide, carbon disulfide, urea, thiourea, formic and acetic acids were studied. All the synthesized compounds were characterized by spectroscopic means and elemental analysis. Compound 4c exhibited 64% and 72% analgesic activity. Also, compound 4b showed 50% and 65% anti-inflammatory activity. Interestingly these compounds showed one-third of ulcer index of the reference aspirin and diclofenac.     

CoMFA and CoMSIA studies of angiotensin (AT1) receptor antagonists

Journal of Molecular Modeling -     

CoMFA and CoMSIA studies of angiotensin (AT1) receptor antagonists

Two 3D-QSAR methods--CoMFA and CoMSIA--were applied to a set of 38 angiotensin receptor (AT1) antagonists. The conformation and alignment of molecules were obtained by a novel method - consensus dynamics. The representation of biological activity, partial charge formalism, absolute orientation of the molecules in the grid, and grid spacing were also studied for their effect on the CoMFA models. The models were thoroughly validated through trials using scrambled activities and bootstrapping. The best CoMFA model had a cross-validated correlation coefficient ( q2) of 0.632, which improved with "region focusing" to 0.680. This model had a "predictive" r2 of 0.436 on a test series that was unique and with little representation in the training set. Although the "predictive" r2 of the best CoMSIA model, which included steric, electrostatic, and hydrogen bond acceptor fields was higher than that of the best CoMFA model, the other statistical parameters like q2, r2, F value, and s were unsatisfactory. The contour maps generated using the best CoMFA model were used to identify the structural features important for biological activity in these compounds.     

Synthesis and biological evaluation of new fluorine substituted derivatives as angiotensin II receptor antagonists with anti-hypertension and anti-tumor effects

The synthesis and pharmaceutical activity of new potent non-tetrazole angiotensin II (Ang II) receptor antagonists were described. These compounds were fluorine substituted derivatives of Losartan, Valsartan and Irbesartan with carboxylic acid group as replacements to the known potent tetrazole moiety at the 2′-biphenyl position. Their activities were evaluated by Ang II receptor binding assay as well as by in vivo assay. All of the synthesized compounds showed nanomolar affinity for the AT₁ receptor subtype. The vivo biological evaluation showed that compounds 1a, 2 and 4 produced a dose-dependent antihypertensive effect both in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Compound 4 especially showed an efficient and long-lasting effect in reducing blood pressure which can last more than 24 h at dose of 10 mg/kg in SHR, which was much better than control Losartan and Valsartan. Compound 4 can also inhibit the prostate cancer in vitro and in vivo. So compound 4 was selected for in-depth investigation as potent, novel and long-lasting non-tetrazole anti-hypertension and anti-tumor drug candidate.     

Synthesis and evaluation of novel angiotensin II receptor 1 antagonists as anti-hypertension drugs

Three new angiotensin II receptor 1 antagonists, 1, 2 and 3 were designed, synthesized and evaluated. The AT₁ receptor-binding assays in vitro showed that all the synthesized compounds had nanomolar affinity for the AT₁ receptor. From which compound 3 was found to be the most potent ligands with an IC₅₀ value of 2.67 ± 0.23 nM. Biological evaluation in vivo revealed that all the compounds could cause significant decrease on MBP in a dose dependent manner in spontaneously hypertensive rats, and compound 3 especially showed an efficient and long-lasting effect in reducing blood pressure, whose maximal response lowered 41 mmHg of MBP at 10 mg/kg and 62 mmHg at 15 mg/kg after oral administration, the significant anti-hypertensive effect lasted beyond 12 h, which is better than the reference compound losartan. The pharmacokinetic experiments showed that compound 3 could be absorbed efficiently and metabolized smoothly both in blood and in tissues in Wistar rats. The acute toxicity assay suggested that it has low toxicity with the LD₅₀ value of 2974.35 mg/kg. These results demonstrate that compound 3 is a potent angiotensin AT₁ receptor antagonist which could be considered as a novel anti-hypertension candidate and deserved for further investigation.     

Superimposition of potent non-peptide AT1 receptor antagonists with angiotensin II

Summary The model of angiotensin II (ANG II) developed in our laboratory using a combination of NMR, fluorescence data and molecular graphics [Matsoukas, J.M. et al., J. Biol. Chem., 269 (1994) 5303] served as a template for a systematic superimposition of potent AT₁ receptor antagonists with ANG II. The key amino acids in this model, tyrosine, phenylalanine and histidine, form a charge-relay system. The studied ANG II AT₁ receptor antagonists were found to accommodate this relay system. The proposed model offers a motivation to synthetic chemists to develop ANG II antagonists that differ from the losartan prototype structure but possess an enhanced biological profile.     

Synthesis and fungicidal activity of 3,5-dichloropyrazin-2(1H)-one derivatives

We synthesized a family of 3,5-dichloropyrazin-2(1H)-one derivatives and assessed their in vitro fungicidal activity against Candida albicans. Compounds 11 and 20 were most active against C. albicans and induced accumulation of reactive oxygen species in this pathogen. Using a genome-wide approach in the yeast Saccharomyces cerevisiae, we demonstrated that genes involved in vacuolar functionality and DNA-related functions play an important role in cellular mechanisms underlying the fungicidal activity of these compounds.     

Effect of angiotensin II non-peptide AT(1) antagonist losartan on phosphatidylethanolamine membranes

Losartan was found to affect both the thermotropic behavior and molecular mobility of dimyristoyl- and dipalmitoyl-phosphatidylcholine membranes (Theodoropoulou and Marsh, Biochim. Biophys. Acta 1461 (1999) 135-146). At low concentrations, the antagonist is located close to the interfacial region of the phosphatidylcholine bilayer while at high mole fractions it inserts deeper in the bilayers. In the present study, we investigated the interactions of losartan with phosphatidylethanolamine membranes using differential scanning calorimetry (DSC), electron spin resonance (ESR) and 31P nuclear magnetic resonance (NMR) spectroscopy. DSC showed that the antagonist affected the thermotropic transitions of dimyristoyl-, dipalmitoyl- and dielaidoyl-phosphatidylethanolamine membranes (DMPE, DPPE and DEPE, respectively). ESR spectroscopy showed that the interaction of losartan with phosphatidylethanolamine membranes is more superficial than in the case of phosphatidylcholine bilayers. Additionally, losartan increased the spin-spin broadening of 12-PESL spin labels in the gel phase of DMPE and DPPE membranes, while in the case of DEPE membranes the opposite effect was observed. (31)P-NMR showed that the antagonist stabilizes the fluid lamellar phase of DEPE membranes relative to the hexagonal H(II) phase. Our results show that losartan affects the thermotropic behavior of phosphatidylethanolamine membranes, while the molecular mobility of the membranes is not affected greatly. Furthermore, its interactions with phosphatidylethanolamine membranes are more superficial than with phosphatidylcholine bilayers.