Comparing Intraocular Pressure, Ocular Blood Flow, and Retinal Nerve Fiber Layer Thickness in Early and Chronic Hypertensives With Normotensives.

PURPOSE: To compare blood pressure (BP), intraocular pressure (IOP), ophthalmic artery flow (OAF) velocity, retinal nerve fiber layer (RNFL) thickness, and visual fields in newly diagnosed hypertension (HT) patients (before treatment), chronic HT (on antihypertensive medications >5 years) and normotensives. METHODS: A prospective, cross-sectional study at a tertiary care centre in India. Three groups of 45 patients each: group 1 - early HT, group 2 - chronic HT, and Group 3 - normotensives, underwent evaluation of BP, IOP by Goldmann applanation tonometry (GAT), OAF velocity by transcranial doppler (TCD), RNFL analysis by spectral-domain optical coherence tomography (SD-OCT), and visual fields. RESULTS: The BP was highest in early HT > chronic HT > normotensives (p < 0.001). The IOP of early HT, chronic HT, and normotensives were 15.87 ± 2.19 mmHg, 13.47 ± 1.92 mmHg, and 15.67 ± SD 1.75 mmHg (p < 0.001). The OAF velocity [peak systolic velocity (PSV), end-diastolic velocity (EDV) in cm/sec] was lowest in chronic HT (30.80 ± 7.05, 8.58 ± 1.58) < early HT (35.47 ± 5.34, 10.02 ± 1.74) < normotensives (36.29 ± 4.43, 10.44 ± 2.29), (p < 0.001). The average RNFL thickness was significantly lower in chronic HT (p = 0.022). The PSV, EDV, and MFV showed significant correlation with IOP (r = 0.247, p = 0.004; r = 0.206, p = 0.016; r = 0.266, p = 0.002) and average RNFL thickness (r = 0.309, p= <0.001; r = 0.277, p = 0.001; r = 0.341, p < 0.001). CONCLUSIONS: Patients with chronic HT demonstrated the lowest retrobulbar flows, IOP and lower RNFL measurements. Lower ocular perfusion may be associated with lower IOP and may be a risk factor for end-organ damage (RNFL) independent of IOP.

Comparing Peribulbar and Topical Anesthesia in Cataract Surgery among Patients with Cardiovascular Disease.

PURPOSE: To compare topical and peribulbar anesthesia in cataract surgery for hemodynamic changes, rate of complications and pain score in patients with cardiovascular disease. METHODS: A prospective comparative study at a tertiary care center in India. Patients >40 years old with treated/controlled hypertension and cardiovascular disease scheduled for cataract surgery under topical or peribulbar anesthesia were recruited. Heart rate, blood pressure, and ophthalmic and systemic complications were noted: preoperatively, immediately after block, intraoperatively, immediately postoperatively and 1 hour postoperatively. A visual analog scale was used to assess the pain score. RESULTS: A total of 150 patients (75 in each group) underwent cataract surgery. There was a significant rise in pulse rate and blood pressure after peribulbar injection and intraoperatively, which gradually reduced to baseline 1 hour after surgery in both groups (p < 0.001), with systolic blood pressure intraoperatively being significantly greater in the peribulbar group (155.49 ±18.14 mmHg vs. 147.95 ±17.71 mmHg, p = 0.01). The topical group had slightly lower visual analog scale scores (1.12 ± 0.99) than the peribulbar group (1.44 ± 0.90, p = 0.04). CONCLUSIONS: Cataract surgery appears safe in patients with adequately controlled cardiovascular disease, and topical anesthesia may be preferable due to noninvasiveness, adequate analgesia, and minimal effect on hemodynamic parameters. Therefore, hemodynamically stable patients of cardiovascular disease undergoing uncomplicated cataract surgery may be counselled for topical anesthesia.

Neutropenic Rat Thigh Infection Model for Evaluation of the Pharmacokinetics/Pharmacodynamics of Anti-Infectives.

The neutropenic mouse infection model is extensively used to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of anti-infective agents. However, it is difficult to evaluate agents following intravenous (i.v.) infusions using this model. Furthermore, in many drug discovery programs, lead identification and optimization is performed in rats, and pharmacology is performed in mice. Alternative models of infection are needed for robust predictions of PK/PD in humans. The rat is an alternative model of infection which can overcome the shortcomings of the mouse model. However, the rat neutropenic thigh infection (NTI) model has not been adequately characterized for evaluation of the PK/PD of anti-infectives. The aim of this study was to characterize the PK/PD of ciprofloxacin against bacterial pathogens in a rat NTI model. We studied the PK/PD relationships of ciprofloxacin against wild-type Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae in neutropenic Wistar rats following administration of 10, 30, and 100 mg/kg as single intravenous boluses and 30- and 60-min infusions. The PK/PD of ciprofloxacin against all four pathogens was AUC/MIC dependent and independent of the duration of administration at 10, 30, and 100 mg/kg. At human-equivalent rat doses, the PK/PD targets of ciprofloxacin achieved in rats for microbiological cure were similar to those reported in human patients. The neutropenic rat thigh infection model can be used to evaluate anti-infective agents intended to be administered as infusions in the clinic, and it complements the mouse model, increasing the robustness of PK/PD predictions in humans. IMPORTANCE Many antibiotics are administered as intravenous infusions in the clinic, especially in intensive care units. Anti-infective drug discovery companies develop clinical candidates that are intended to be administered as i.v. infusions in the clinic. However, there are no well-characterized models with which they can evaluate the PK/PD of the candidates following i.v. infusions. The neutropenic rat thigh infection model reported in this study helps in evaluating anti-infective agents that are intended to be administered as i.v. infusions in the clinic. The rat model is useful for simulating the clinical conditions for i.v. infusions for treatment of infections, such as acute bacterial skin and skin structure, lung, and urinary tract infections. This model is predictive of efficacy in humans and can serve as an additional confirmatory model, along with the mouse model, for determining the proof of concept and for making robust predictions of efficacy in humans.

Effect of Blood Pressure Reduction on Intraocular Pressure and Ophthalmic Artery Blood Flow Velocity in Hypertension.

Purpose: To evaluate the effect of reducing blood pressure (BP) by atenolol and amlodipine on (1) intraocular pressure (IOP) and (2) ophthalmic artery blood flow (OAF) velocity in new hypertensives. Methods: A prospective, observational cohort study conducted at a tertiary care center in India after IRB approval. New hypertensives treated with atenolol 25 mg or amlodipine 5 mg were divided into 2 groups of 30 patients each. BP, IOP by Goldmann applanation tonometry and OAF velocity by transcranial doppler sonography was performed before medication and post medication on day 1, 7, and 30. Results: There was a significant decrease in IOP with both drugs; the effect was greater with atenolol. Atenolol: premedication IOP - 16.06 ± 2.13 mmHg and day 30-12.46 ± 1.94 (22.4%) [P < 0.001], amlodipine: premedication IOP-15.13 ± 2.55 mmHg and day 30- 13.06 ± 2.14 (13.68%) [P < 0.001]. A decrease of 0.5 mmHg in IOP with every 10 mmHg (95% CI: 0.121-0.826, P value = 0.01) decrease in systolic BP was noted after oral atenolol. The OAF peak systolic velocity and mean flow velocity were equally reduced with both drugs (P < 0.001). The end-diastolic velocity, reduced only with atenolol (P = 0.049) but returned to baseline with amlodipine at 1 month. Conclusions: BP reduction by atenolol and amlodipine led to decreases in IOP and OAF velocity, greater with atenolol. The IOP decrease was likely due to reduced blood flow. A slight decrease in the diastolic flow of the ophthalmic artery was noted with atenolol.

A critical review on the formation, fate and degradation of the persistent organic pollutant hexachlorocyclohexane in water systems and waste streams.

The environmental impacts of persistent organic pollutants (POPs) is an increasingly prominent topic in the scientific community. POPs are stable chemicals that are accumulated in living beings and can act as endocrine disruptors or carcinogens on prolonged exposure. Although efforts have been taken to minimize or ban the use of certain POPs, their use is still widespread due to their importance in several industries. As a result, it is imperative that POPs in the ecosystem are degraded efficiently and safely in order to avoid long-lasting environmental damage. This review focuses on the degradation techniques of hexachlorocyclohexane (HCH), a pollutant that has strong adverse effects on a variety of organisms. Different technologies such as adsorption, bioremediation and advanced oxidation process have been critically analyzed in this study. All 3 techniques have exhibited near complete removal of HCH under ideal conditions, and the median removal efficiency values for adsorption, bioremediation and advanced oxidation process were found to be 80%, 93% and 82% respectively. However, it must be noted that there is no ideal HCH removal technique and the selection of removal method depends on several factors. Furthermore, the fates of HCH in the environment and challenges faced by HCH degradation have also been explained in this study. The future scope for research in this field has also received attention.

Nano-adsorbents an effective candidate for removal of toxic pharmaceutical compounds from aqueous environment: A critical review on emerging trends.

Advancements in medical research has resulted in the modernization of healthcare facilities, subsequently leading to a higher level of production and usage of pharmaceuticals to sustain better quality of life. Pharmaceutical active compounds (PhACs) possess high genotoxicity and eco-toxicity thus presenting numerous side effects to living beings on long-term exposure. The fate and toxicity of PhACs were explored in detail, aiming to elucidate their occurrence and transmission in wastewater treatment systems (WWTPs). Adsorption of pharmaceutical compounds using Nano-adsorbents has gained momentum in recent years owing to their low-cost, high surface area and effectiveness. This review has been conducted in order to widen the utilization of Nano adsorbents in the adsorption of pharmaceutical compounds with a focus on the aqueous environment. The synthesis routes and properties of Nano-adsorbents for removal of PhACs were assessed in a comprehensive way. The recovery and reuse ability of nano-adsorbents also forms an integral part of its application in the removal of PhACs and has hence been delineated.

Anaerobic digestate water for Chlorella pyrenoidosa cultivation and employed as co-substrate with cow dung and chicken manure for methane and hydrogen production: A closed loop approach.

In rural India, unpleasant atmosphere, anthropogenic gas emission, air and soil pollution are caused due to disposal of livestock's wastes (cow dung and chicken waste) in open environment. This study provides zero emission concept for waste disposal and value addition of these wastes for renewable green energy production. In this study, biogas production was carried out with varying proportion of cow dung to chicken waste (1:0, 0:1, 1:1, 2:1, 1:2, 3:1 and 1:3) for duration of 40 days. Chlorella pyrenoidosa was cultivated from digestate water and used as co-substrate in digester in varying proportions (2:1:1, 2:1:2 and 2:1:3) to study its role on biogas distribution. The effect of pH, feedstock ratio, time and C/N ratio for biogas production were evaluated. The maximum methane and hydrogen yield was 68% (30th day) and 29% (10th day) for 2:1:2 ratio respectively. The slurry possessed nitrogen (1.7%), phosphate (0.8%) and potassium (0.4%) respectively.

Hydrothermal liquefaction of Scenedesmus obliquus using a novel catalyst derived from clam shells: Solid residue as catalyst for hydrogen production.

This study explores the catalytic application of waste clam shell in hydrothermal liquefaction (HTL) of microalgae (Scenedesmus obliquus) for liquid hydrocarbons production. Novel catalyst (calcium hydroxide) was derived from clam shells. Catalytic HTL was performed at varying temperature of 240-320 °C for catalyst load (0.2-1 wt%) at a reaction time of 60 min. Bio-oil yield was maximum (39.6 wt%) at a temperature of 300 °C for catalyst load of 0.6 wt% at a reaction time of 60 min with calorific value of 35.01 MJ/kg. Compounds like phenols, aromatic hydrocarbons, acids and aldehydes were detected in bio-oil through Gas Chromatography Mass Spectrophotometry (GC-MS). Gasification of microalgae with waste solid residue obtained from HTL was carried out for hydrogen production. Valuable hydrogen gas production was maximum (37 wt%) at a temperature of 400 °C for 3 wt% of solid residue. Water-gas shift, methanation and steam reforming reactions favoured the hydrogen gas production.

Pharmacokinetics/Pharmacodynamics (PK/PD) of Ciprofloxacin in the Complicated Urinary Tract Infection (cUTI) Model in Diabetic Mice.

BACKGROUND: The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections (cUTI). OBJECTIVE: The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients. METHODS: Streptozotocin induced diabetic female BALB/c mice were infected transurethrally with Escherichia coli. Four hours post infection, CIP oral doses of 3, 10, 30,100, and 300 mg/kg, were administered as single doses (for PK and dose response) and repeated doses (PD and PK/PD). Bacterial burden in kidneys, bladder, urine, body temperature, and other clinical signs were assessed twenty-four hours post-treatment. RESULTS: CIP displayed linear PK with dose proportional increase in Cmax and AUCinf in plasma. In PD time course studies, CIP showed rapid onset, intensity and duration of anti-bacterial effect in target tissues. In intrinsic PD studies, CIP showed a maximum effect at plasma AUC/MIC=1705 (300 mg/kg, twice daily) for bacterial load in bladder (r2=0.979), kidney (r2=0.951) and rectal temperature (r2=0.67). A plasma AUC/MIC ratio of 412 was associated with maximum PD effect of Imax=3.7 Log10CFU/bladder and Imax=1.97 Log10CFU/kidney. In dose fractionation studies, plasma AUC/MIC ratio showed highest correlation with efficacy in bladder (r2=0.77) and kidney (r2=0.80) followed by Cmax/MIC ratio in bladder (r2=0.68). CONCLUSION: Plasma AUC/MIC showed the highest correlation with the efficacy of Ciprofloxacin on E. coli in diabetic mice with cUTI.

Linear Cyclodextrin Polymer Prodrugs as Novel Therapeutics for Niemann-Pick Type C1 Disorder.

Niemann-Pick Type C1 disorder (NPC) is a rare lysosomal storage disease characterized by the accumulation of cholesterol in lysosomes. NPC has no FDA approved treatments yet, however 2-hydroxypropyl-ß-cyclodextrin (HPßCD) has shown efficacy for treating the disease in both mouse and feline NPC models and is currently being investigated in late stage clinical trials. Despite promising results, therapeutic use of HPßCD is limited by the need for high doses, ototoxicity and intrathecal administration. These limitations can be attributed to its poor pharmacokinetic profile. In the attempt to overcome these limitations, we have designed a ß-cyclodextrin (ßCD) based polymer prodrugs (ORX-301) for an enhanced pharmacokinetic and biodistribution profile, which in turn can potentially provide an improved efficacy at lower doses. We demonstrated that subcutaneously injected ORX-301 extended the mean lifespan of NPC mice at a dosage 5-fold lower (800 mg/kg, body weight) the HPßCD dose proven efficacious (4000 mg/kg). We also show that ORX-301 penetrates the blood brain barrier and counteracts neurological impairment. These properties represent a substantial improvement and appear to overcome major limitations of presently available ßCD-based therapy, demonstrating that this novel prodrug is a valuable alternative/complement for existing therapies.

Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy.

The mechanism of efflux is a tour-de-force in the bacterial armoury that has thwarted the development of novel antibiotics. We report the discovery of a novel chemical series with potent antibacterial properties that was engineered to overcome efflux liability. Compounds liable to efflux specifically via the Resistance Nodulation and cell Division (RND) pump, AcrAB-TolC were chosen for a hit to lead progression. Using structure-based design, the compounds were optimised to lose their binding to the efflux pump, thereby making them potent on wild-type bacteria. We discovered these compounds to be pro-drugs that require activation in E. coli by specific bacterial nitroreductases NfsA and NfsB. Hit to lead chemistry led to the generation of compounds that were potent on wild-type and multi-drug resistant clinical isolates of E. coli, Shigella spp., and Salmonella spp. These compounds are bactericidal and efficacious in a mouse thigh infection model.

Oral manifestations of dengue fever

Background: Dengue is a life­threatening viral infection which has become an epidemic in India in the postmonsoon period (August­November). It mostly associated with nonspecific fever and rashes, arthralgia, myalgia, and thrombocytopenia in severe cases. Objective: This study aimed to study the oral manifestations of dengue fever and to observe the various features of oral presentation then to validate the significance and importance of oralmanifestation in the diagnosis of dengue fever.Materials and Methods: Patients meeting the inclusion criteria were subjected to detailed history, oral examination, and relevant investigations. Results: Intraoral manifestations were present in 24 (48%) patients, anf these included petechiae (29.2%), bleeding gums (16.6%), ulcer (4.2%), dryness of mouth (4.2%), and combined features (45.8%). Extraoral manifestations were present in 4% of the cases. Conclusion: This study highlights the thrombocytopenia related oral haemosrrhagic manifestations of dengue fever

Metabolism and Disposition of Pacritinib (SB1518), an Orally Active Janus Kinase 2 Inhibitor in Preclinical Species and Humans.

The ADME of Pacritinib (SB1518), an orally active JAK 2 inhibitor, was investigated in vitro and in vivo in preclinical species and humans. Pacritinib showed ~5 fold higher affinity to human plasma proteins relative to mouse in vitro. It was metabolized by human CYP3A4 in vitro, and did not significantly induce CYP3A and 1A2 in human hepatocytes. In vitro metabolism studies with mouse and human liver microsomes showed the presence of four major metabolites of Pacritinib -M1 (oxidation), M2 (dealkylation), M3 (oxidation), M4 (reduction). The in vitro and in vivo metabolic patterns observed in mice and humans were in good agreement. Qualitatively and quantitatively, none of the metabolites formed in vivo was >10% of Pacritinib in mouse, dog and humans. Pacritinib showed systemic clearance of 8.0, 1.6, 1.6 l/h/kg, volume of distribution of 14.2, 7.9, 8.5 l/kg, t1/2 of 5.6, 6.0, 4.6 h, and oral bioavailability of 39, 10, and 24% in mouse, rat and dog, respectively. In radiolabeled mass balance and QWBA studies in mice, ~91% of the dose was recovered in feces, suggesting biliary clearance, and maximum radioactivity was seen in the gastrointestinal tract followed by the kidney, heart and low activity in the brain. The relatively high exposures of Pacritinib in humans might be attributed to its very high plasma protein binding, low metabolic and/or biliary clearance.

VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer.

Dysregulation of the PI3K/mTOR pathway, either through amplifications, deletions, or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. Moreover, this pathway activation is a poor prognostic marker for many tumor types and confers resistance to various cancer therapies. Here, we describe VS-5584, a novel, low-molecular weight compound with equivalent potent activity against mTOR (IC(50) = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC(50): PI3Kα = 16 nmol/L; PI3Kß = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kδ = 42 nmol/L, without relevant activity on 400 lipid and protein kinases. VS-5584 shows robust modulation of cellular PI3K/mTOR pathways, inhibiting phosphorylation of substrates downstream of PI3K and mTORC1/2. A large human cancer cell line panel screen (436 lines) revealed broad antiproliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive toward VS-5584 treatment. VS-5584 exhibits favorable pharmacokinetic properties after oral dosing in mice and is well tolerated. VS-5584 induces long-lasting and dose-dependent inhibition of PI3K/mTOR signaling in tumor tissue, leading to tumor growth inhibition in various rapalog-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGF receptor inhibitor in a gastric tumor model. The unique selectivity profile and favorable pharmacologic and pharmaceutical properties of VS-5584 and its efficacy in a wide range of human tumor models supports further investigations of VS-5584 in clinical trials.

SB1578, a novel inhibitor of JAK2, FLT3, and c-Fms for the treatment of rheumatoid arthritis.

SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in multiple lymphoma subtypes.

PURPOSE: The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma. PATIENTS AND METHODS: Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks. RESULTS: Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration-time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%. CONCLUSION: SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.

Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor.

SB1317 (TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-cancer agent. SB1317 was soluble, highly permeable in Caco-2 cells, and showed > 99% binding to plasma from mice, dog and humans. It was metabolically stable in human and dog liver microsomes relative to mouse and rat. SB1317 was mainly metabolized by CYP3A4 and CY1A2 in vitro. SB1317 did not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 µM). SB1317 did not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro. The metabolic profiles in liver microsomes from preclinical species were qualitatively similar to humans. In pharmacokinetic studies SB1317 showed moderate to high systemic clearance (relative to liver blood flow), high volume of distribution ( > 0.6 L/kg), oral bioavailability of 24%, ∼ 4 and 37% in mice, rats and dogs, respectively; and extensive tissue distribution in mice. The favorable ADME of SB1317 supported its preclinical development as an oral drug candidate.

Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis.

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.

Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase inhibitor, and prediction of human pharmacokinetics.

The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino) ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat. The major metabolites formed in human liver microsomes were also observed in preclinical species. Human cytochrome P450 (P450) phenotyping showed that SB939 was primarily metabolized by CYP3A4 and CYP1A2. SB939 did not significantly inhibit human CYP3A4, 1A2, 2D6, and 2C9 (>25 µM) but inhibited 2C19 (IC(50) = 5.8 µM). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between ∼84 and 94%. The blood-to-plasma ratio was ∼1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l · h(-1) · kg(-1) and high volume of distribution at steady state (>0.6 l/kg) of 3.5, 1.7, and 4.2 l/kg in mouse, rat, and dog, respectively. The oral bioavailability was 34, 65, and ∼3% in mice, dogs, and rats, respectively. The predicted oral PK profile and parameters of SB939, using Simcyp and allometric scaling, were in good agreement with observed data in humans. Simcyp predictions showed lack of CYP3A4 and 2C19 drug-drug interaction potential for SB939. In summary, the preclinical ADME of SB939 supported its preclinical and clinical development as an oral drug candidate.