Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor.

The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.

Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors.

This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.

The Subjective Global Assessment: a review of its use in clinical practice.

Many methods of evaluating malnutrition have been proposed that combine multiple components such as dietary and medical history, amount of weight loss, biochemical variables, and anthropometry. The Subjective Global Assessment (SGA), first described by Baker et al in 1982, SGA was introduced to assess the patient for malnutrition at the bedside, without the need for precise body composition analysis. Since it was developed, the SGA has been used in various different patient populations, including surgical and oncology patients. It remains the most reliable and efficient method of nutrition assessment. The authors present a review of the SGA and how it has been used in a variety of areas within medicine.

Microscopic colitis-defining incidence rates and risk factors: a population-based study.

BACKGROUND & AIMS: The burden and determinants of microscopic colitis (MC) in North America are inadequately defined. We determined the incidence rate of and risk factors for MC in a well-defined North American population. METHODS: A population-based cohort study was conducted between April 1, 2002, and March 31, 2004. All adults with a pathologic diagnosis of MC were identified and comprehensive chart review was undertaken to confirm the diagnosis and identify risk factors. Category-specific risks for developing MC were reported as rate ratios (RRs) with exact 95% confidence intervals (CIs). RESULTS: MC was identified in 164 individuals for an annual incidence rate of 10.0 per 100,000 person-years (lymphocytic colitis, 5.4; collagenous colitis, 4.6 per 100,000). Patients older than the age of 65 were more than 5 times more likely to develop MC (RR, 5.6; 95% CI, 4.0-7.7). Women were at higher risk of acquiring MC for both collagenous colitis (RR, 3.44; 95% CI, 2.07-5.97) and lymphocytic colitis (RR 6.29; 95% CI, 3.21-13.74). Elderly women with a history of malignancy were associated with a higher risk of MC (RR, 3.59; 95% CI, 1.68-7.01), as were patients with celiac disease (RR, 7.9; 95% CI, 4.0-14.2) and hypothyroidism (RR, 6.1; 95% CI, 3.5-10.0). CONCLUSIONS: This was a large population-based cohort study of MC and our incidence rates were consistent with previously reported population-based studies in North America and Europe. An increased incidence of MC was observed in several disease states with the novel finding of an increased risk of MC with malignancy.

Controlled porosity osmotic pump-based controlled release systems of pseudoephedrine. I. Cellulose acetate as a semipermeable membrane.

A controlled porosity osmotic pump-based drug delivery system has been described in this study. Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channeling agents in the coating. The usual dose of pseudoephedrine is 60 mg to be taken three or four times daily. It has a short plasma half life of 5-8 h. Hence, pseudoephedrine was chosen as a model drug with an aim to develop a controlled release system for a period of 12 h. Sodium bicarbonate was used as the osmogent. The effect of different ratios of drug:osmogent on the in-vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. Different channeling agents tried were diethylphthalate (DEP), dibutylphthalate (DBP), dibutylsebacate (DBS) and polyethyleneglycol 400 (PEG 400). The effect of polymer loading on in-vitro drug release was studied. It was found that drug release rate increased with the amount of osmogent due to the increased water uptake, and hence increased driving force for drug release. This could be retarded by the proper choice of channeling agent in order to achieve the desired zero order release profile. Also the lag time seen with tablets coated using diethylphthalate as channeling agent was reduced by using a hydrophilic plasticizer like polyethyleneglycol 400 in combination with diethylphthalate. This system was found to deliver pseudoephedrine at a zero order rate for 12 h. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per ICH guidelines at different temperature and humidity conditions.

Once daily sustained release tablets of venlafaxine, a novel antidepressant.

Venlafaxine is a unique antidepressant that differs structurally from other currently available antidepressants. Sustained release tablets of venlafaxine to be taken once daily were formulated with venlafaxine hydrochloride equivalent to 75 mg of venlafaxine base. Matrix system based on swellable as well as non-swellable polymers was selected for sustaining the drug release. Different polymers viz. hydroxypropylmethylcellulose (HPMC), cellulose acetate, Eudragit RSPO, ethylcellulose etc. were studied. Combinations of non-swellable polymers with HPMC were also tried in order to get the desired sustained release profile over a period of 16 h. The effect of drug to polymer ratio on in vitro release was studied. The marketed formulation was evaluated for different parameters such as appearance, weight variation, drug content and in vitro drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. These were evaluated for appearance, weight variation, thickness, hardness, friability, drug content and in vitro drug release at selected time intervals. In vivo studies were carried out for the optimized formulation in 12 healthy human volunteers and the pharmacokinetic parameters were compared with the marketed one.

Stability indicating LC method for the estimation of venlafaxine in pharmaceutical formulations.

A rapid, selective and stability indicating high performance liquid chromatographic method was developed and validated for the estimation of venlafaxine in pharmaceutical dosage forms. The analysis was done on a Spherisorb C8 (4.6 x 250 mm, 5 microm) column. The mobile phase consisted of acetonitrile:sodium dihydrogen orthophosphate [0.04 M], pH 6.8 (75:25) at a flow rate of 1.5 ml/min. Detection was carried out at a wavelength of 224 nm. The developed method was found to give good separation between the pure drug and the degraded product. The polynomial regression data for the calibration plots showed good linear relationship in the concentration range of 1-10 microg/ml with r=0.9999. The method was validated for precision, accuracy, ruggedness and recovery. The minimum detectable and minimum quantifiable amounts were found to be 150 and 600 ng/ml, respectively. The drug was stable under basic and oxidative conditions. However, the sample treated with acid showed an additional peak at a retention time of 4.32 min other than the main peak at a retention time of 5.32 min. Statistical analysis proves that the method is reproducible and selective for the estimation of venlafaxine. As the method could effectively separate the drug from the degradation product, it can be employed as a stability indicating one.