Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.

Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.

Design, Synthesis, and Pharmacological Evaluation of Second-Generation Tetrahydroisoquinoline-Based CXCR4 Antagonists with Favorable ADME Properties.

CXCR4 is a G-protein-coupled receptor that interacts with its cognate ligand, CXCL12, to synchronize many physiological responses and pathological processes. Disruption of the CXCL12-CXCR4 circuitry by small-molecule antagonists has emerged as a promising strategy for cancer intervention. We previously disclosed a hit-to-lead effort that led to the discovery of a series of tetrahydroisoquinoline-based CXCR4 antagonists exemplified by the lead compound TIQ15. Herein, we describe our medicinal-chemistry efforts toward the redesign of TIQ15 as a result of high mouse-microsomal clearance, potent CYP2D6 inhibition, and poor membrane permeability. Guided by the in vitro ADME data of TIQ15, structural modifications were executed to provide compound 12a, which demonstrated a reduced potential for first-pass metabolism while maintaining CXCR4 potency. Subsequent SAR studies and multiparameter optimization of 12a resulted in the identification of compound 25o, a highly potent, selective, and metabolically stable CXCR4 antagonist possessing good intestinal permeability and low risk of CYP-mediated drug-drug interactions.

Applications of Higenamine in pharmacology and medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum has been used as local and traditional medicines in many asian regions for the treatment of various diseases such as collapse, syncope, painful joints, oedema, bronchial asthma et al. Higenamine, a plant-based alkaloid, was initially isolated from Aconitum and identified as the active cardiotonic component of Aconitum. It has been tested as a candidate of pharmacologic stress agent in the detection of coronary artery diseases (CADs) and now researchers have just accomplished the phase III clinical studies successfully in China. Besides, a large number of studies have revealed the various pharmacological properties and potentially multi-spectral medical applications of higenamine. However, to date, no comprehensive review on higenamine has been published. AIM OF THE REVIEW: This present paper aims to compile a comprehensive update regarding the biochemistry, pharmacokinetic features, pharmacological activities, clinical and potential clinical uses and toxicities on higenamine with the ultimate objective of providing a guide for future research on this drug. MATERIALS AND METHODS: The selection of relevant data was made through a search using the keyword "higenamine" in "Web of science", "Pubmed", and "China Knowledge Resource Integrated (CNKI)". Information was also acquired from local classic herbal literature, government reports and conference papers. RESULTS: In addition to Aconitum, higenamine also exists in many other plants including Tinospora crispa, Nandina domestica THUNBERG, Gnetum Parvifolium C.Y. Cheng, sarum Heterotropoides,Nelumbo nucifera,N.nucifera. The pharmacokinetic studies conducted in animals and humans showed that higenamine conformed to a two-compartment pharmacokinetic model. Studies over the last four decades on higenamine have revealed its various pharmacological properties such as positive inotropic and chronotropic effect, activating slow channel effect, vascular and tracheal relaxation effect, anti-thrombotic, anti-apoptotic and anti-oxidative effect, anti-inflammatory and immunomodulatory effect. This phytochemical constituent has shown its potential therapeutic effects for diseases like heart failure, disseminated intravascular coagulation (DIC), shock, arthritis, asthma, ischemia/reperfusion (I/R) injuries and erectile dysfunction. CONCLUSIONS: Extensive basic and clinical studies on higenamine showed valuable therapeutic effects on different disorders. However, the underlying mechanisms of higenamine have not been established. Therefore, the safety, tolerability and efficacy of higenamine are as yet, not fully understood. Additionally, some of the studies were small sample-sized and unreliable. To sum up, there is a need for deeper investigation in the mechanisms of higenamine action, as well as well-designed preclinical and clinical trials studies to test the safety and clinical value of the drug.

Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3- and 4-methyl substituents.

The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a-c, and 4d-f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [(35)S]GTPγS binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective κ opioid receptor antagonists.

Dauricine can inhibit the activity of proliferation of urinary tract tumor cells.

OBJECTIVE: To explore the anti-tumor effects of asiatic moonseed rhizome extraction-dauricine on bladder cancer EJ cell strain, prostate cancer PC-3Mcell strain and primary cell culture system. METHODS: The main effective component-phenolic alkaloids ofMenispermum dauricum was extracted and separated from asiatic moonseed rhizome by chemical method. MTT method was used to detect dauricine anti-tumor effect. RESULTS: Dauricine had an obvious proliferation inhibition effect on the main tumor cells in urinary system. The minimum drug sensitivity concentration was between 3.81-5.15 µg/mL, and the inhibition ratio increased with the increase of concentration. CONCLUSIONS: Dauricine, the main effective component extracted from asiatic moonseed rhizome, had a good inhibition effect on tumor cells in urinary system. At the same time, Dauricine has certain inhibition effects on the primary cultured tumor cell.

Determination of higenamine in human plasma and urine using liquid chromatography coupled to positive electrospray ionization tandem mass spectrometry.

Higenamine is an active ingredient of Aconite root in Chinese herbal medicine and might be used as a new agent for a pharmaceutical stress test and was approved to undergo clinical pharmacokinetic study. Therefore, there exists a need to establish a sensitive and rapid method for the determination of higenamine in human plasma and urine. This paper described a sensitive and rapid method based on liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the determination of higenamine in human plasma and urine. Solid-phase extraction (SPE) was used to isolate the compounds from biological matrices followed by injection of the extracts onto an Atlantis dC18 column with isocratic elution. The mobile phase was 0.05% formic acid in water-methanol (40:60, v/v). The mass spectrometry was carried out using positive electrospray ionization (ESI) and data acquisition was carried out in the multiple reaction monitoring (MRM) mode. The method was fully validated over the concentration range of 0.100-50.0 ng/mL and 1.00-500 ng/mL in plasma and urine, respectively. The lower limits of quantification (LLOQs) were 0.100 and 1.00 ng/mL in plasma and urine, respectively. Inter- and intra-batch precision was less than 15% and the accuracy was within 85-115% for both plasma and urine. Extraction recovery was 82.1% and 56.6% in plasma and urine, respectively. Selectivity, matrix effects and stability were also validated in human plasma and urine. The method was applied to the pharmacokinetic study of higenamine hydrochloride in Chinese healthy subjects.

Wide-spectrum characterization of trabectedin: biology, clinical activity and future perspectives.

Ecteinascidin-743 (trabectedin, Yondelis((R)); PharmaMar, Madrid, Spain), a 25-year-old antineoplastic alkylating agent, has recently shown unexpected and interesting mechanisms of action. Trabectedin causes perturbation in the transcription of inducible genes (e.g., the multidrug resistance gene MDR1) and interaction with DNA repair mechanisms (e.g., the nucleotide excision repair pathway) owing to drug-related DNA double strand breaks and adduct formation. Trabectedin was the first antineoplastic agent from a marine source (namely, the Caribbean tunicate Ecteinascidia turbinata) to receive marketing authorization. This article summarizes the mechanisms of action, the complex metabolism, the main toxicities, the preclinical and clinical evidences of its antineoplastic effects in different types of cancer and, finally, the future perspectives of this promising drug.

Quinaprilat: a review of its pharmacokinetics, pharmacodynamics, toxicological data and clinical application.

BACKGROUND: Quinaprilat is an ACE inhibitor for intravenous use especially in patients with arterial hypertension or chronic heart failure. In contrast to the oral prodrug quinapril, it has not been approved for clinical application. OBJECTIVE: In this review, the pharmacokinetic and pharmacodynamic profile of quinaprilat as well as toxicological data and results of preclinical and clinical studies are summarized. METHODS: In a PubMed search for the terms "quinaprilat" and "quinapril", literature relevant for this review was selected. RESULTS: Quinaprilat is a potent nonsulfhydryl selective ACE inhibitor with a short elimination half-life of 2 - 3 h, but due to slow dissociation from tissue ACE, once daily dosing is sufficient for effective ACE inhibition. Quinaprilat is excreted mainly in urine. In long-term animal studies, quinaprilat was not teratogenic, mutagenic or carcinogenic. However, due to the risk of fetal and neonatal morbidity and death, it should not be administrated in pregnancy. Quinaprilat is characterized by an excellent safety profile; adverse events occur infrequently and are rarely serious. CONCLUSION: Quinaprilat is an attractive ACE inhibitor, which potently inhibits tissue ACE.

Synthesis and SAR of 1,2,3,4-tetrahydroisoquinolin-1-ones as novel G-protein-coupled receptor 40 (GPR40) antagonists.

The development of a series of novel 1,2,3,4-tetrahydroisoquinolin-1-ones as antagonists of G protein-coupled receptor 40 (GPR40) is described. The synthesis, in vitro inhibitory values for GPR40, in vitro microsomal clearance and rat in vivo clearance data are discussed. Initial hits displayed high rat in vivo clearances that were higher than liver blood flow. Optimization of rat in vivo clearance was achieved and led to the identification of 15i, whose rat oral pharmacokinetic data is reported.

Validation of 8-[123I]iodo-L-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid as an imaging agent for prostate cancer in experimental models of human prostate cancer.

INTRODUCTION: Very few tracers are currently available for the detection and staging of prostate cancer with positron emission tomography and single-photon emission computed tomography. This study evaluates the potential of 8-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid [ITIC(OH)] as an imaging agent for prostate cancer in experimental models of human prostate cancer. METHODS: ITIC(OH) was prepared by the IODO-GEN method, with 82+/-7% radiochemical yield and >99% radiochemical purity after high-performance liquid chromatography. Thereafter, ITIC(OH) was examined in CD-1 nu/nu mice engrafted with human PC-3 and DU-145 prostate cancer in the flank or orthotopically in the prostate. Bioevaluation involved examination of the in vivo stability and uptake characteristics of ITIC(OH) into tumors and different organs by dynamic in vivo analysis and gamma counting of organs of interest after dissection. RESULTS: ITIC(OH) showed good in vivo stability for biological investigations and was primary cleared through urine. In vivo, ITIC(OH) accumulated highly and specifically in tumors, reaching 13.6+/-2.1% to 16.2+/-2.5% injected dose per gram (ID/g) in heterotopic tumors compared with 14.8+/-2.6% and 17.6+/-3.4% ID/g in orthotopic tumor engrafts at 60 and 240 min postinjection, respectively. In contrast, radioactivity uptake in the blood, spleen, liver and gastrointestinal tract was moderate and decreased with time, resulting in marked tumor-to-background and excellent visualization of tumors. CONCLUSION: These results suggest that ITIC(OH) is a promising candidate as radiotracer for detecting prostate cancer and warrants further studies in patients to ascertain its potential as an imaging agent for clinical use.

Synthesis of a novel class of fatty acids-derived isoquinolines.

Two series of novel tetrahydroisoquinoline derivatives bearing at C-1 position a carbon chain derived from fatty acids were prepared employing two complementary synthetic methodologies. The Pictet-Spengler condensation was performed on myristyl, palmityl, stearyl and oleyl aldehydes, whereas the Bischler-Napieralski cyclization used pelargonic, stearic, linolenic and arachidonic acids. The ability to apply both methods allows further labeling of the final 1-substituted-1,2,3,4-tetrahydroisoquinolines for biological studies.

Preclinical pharmacokinetic properties of the P-glycoprotein inhibitor GF120918A (HCl salt of GF120918, 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-4-acridine-carboxamide) in the mouse, rat, dog, and monkey.

GF120918A, the HCl salt of GF120918 (9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl) ethyl]phenyl]-4-acridine-carboxamide), has been used both in vitro and in vivo as a tool inhibitor of P-glycoprotein (Pgp) to investigate the role of transporters in the disposition of various test molecules. However, to date, a detailed description of the preclinical pharmacokinetic properties of GF120918A has not been published. This investigation was performed to evaluate in vitro and in vivo pharmacokinetic properties of GF120918A in the mouse, rat, dog, and monkey and to evaluate the in vivo efficacy of GF120918A in modulating absorption and systemic exposure in the monkey. GF120918A demonstrated reasonable absorption and systemic exposure in each of the species studied, however, in rodents, administration of 300 mg/kg afforded a substantially less than linear increase in systemic exposure compared with 30 mg/kg. In accordance with its intestinal and hepatic exposure and potency against P-glycoprotein, GF120918A demonstrated marked modulation of erythromycin systemic exposure in the monkey, with no effect on propranolol, a negative control molecule. In vitro, GF120918A demonstrated high plasma protein binding across species, although a definitive protein binding evaluation was precluded by poor recovery, particularly in buffer and in mouse, rat, and dog plasma. GF120918A did not demonstrate potent inhibition of several human cytochrome P450 enzymes evaluated in vitro, with IC(50) values well above concentrations anticipated to be achieved in vivo. Together, these data confirm the utility of GF120918A as a tool P-glycoprotein inhibitor in preclinical species and offer additional guidance on preclinical dose regimens likely to produce P-glycoprotein-mediated effects.

Pharmacokinetic-pharmacodynamic modeling of daurisoline and dauricine in beagle dogs.

AIM: To study the combined pharmacokinetic-pharmacodynamic (PK-PD) model of daurisoline and dauricine, and compare their effects on cardiac electrophsiology, blood pressure, and hemodynamics in beagle dogs. METHODS: The plasma drug concentration was determined by the reversed-phase HPLC method and the effects on cardiac and hemodynamics were recorded by polygraph. The pharmacokinetic and PK-PD model parameters were calculated. RESULTS: The pharmacokinetics were best fitted to a two-compartment open model, and the relationship between effect and effect compartment concentration of both drugs could be represented by the sigmoid-E(max) model. There were no significant differences in main pharmacokinetics and PK-PD parameters between the two drugs. CONCLUSION: No statistically different kinetic disposition characteristics and potencies of inhibitory effects on myocardial function of daurisoline and dauricine were found in beagle dogs.