Xue-Qing Chen

Miniature device for aqueous and non-aqueous solubility measurements during drug discovery.

AbstractPurpose. A miniature device was developed for the measurement of aqueous and non-aqueous equilibrium solubility during drug discovery. The solubility values obtained using the miniature device were compared to those obtained using the conventional shake-flask method. Methods. The aqueous solubility of six structurally diverse compounds, the solubility of carbamazepine in various cosolvent systems, and the pH-solubility profile of saquinavir were determined using the miniature device. The device contains a multichannel cartridge pump and a Tygon tubing that is mounted on the pump with two ends linked by a syringe filter. The drug slurry was filled into the tubing and circulated inside, continually passing through the syringe filter. At the end of the experiment, the filtrate was collected and analyzed directly by High-Pressure Liquid Chromatography (HPLC). The solubility was also determined by the shake-flask method. Results. The solubility values determined by the miniature device were in good agreement with those measured by the conventional shake-flask method. Conclusions. The miniature device provides a unique way of testing aqueous and non-aqueous equilibrium solubility in a microscale setting. With ≈1 mg of compound, it is possible to determine the entire pH-solubility profile. The device is useful for solubility screening during lead optimization and candidate selection in early drug discovery, when compound supply is limited. It can also be used for screening solubility in non-aqueous systems to select vehicles for preclinical in vivo studies.

Diphenylpyridylethanamine (DPPE) derivatives as cholesteryl ester transfer protein (CETP) inhibitors.

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.

Discovery of 4-Aryl-7-Hydroxyindoline-Based P2Y1 Antagonists as Novel Antiplatelet Agents

Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y12 and P2Y1. Blocking P2Y12 receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y1 antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y12 inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y1 antagonist, 1. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y12 antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y1 antagonism as a promising new antiplatelet target.

Oral Delivery of Highly Lipophilic Poorly Water-Soluble Drugs: Spray-Dried Dispersions to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a P2Y1 Antagonist

BMS-B is a highly lipophilic compound (clog P 7.72) with poor aqueous solubility (<10 ng/mL at pH 1 and 6.5). The compound exhibits low bioavailability in preclinical species when dosed as cosolvent solution formulations, with reduced exposure upon dose escalation. The purpose of this study was to evaluate spray-dried dispersions (SDDs) for enhancing oral exposure and enabling toxicology studies of BMS-B. SDD solids of BMS-B were prepared with 10%-25% drug in hydroxypropyl methylcellulose acetate succinate and showed an enhanced dissolution profile relative to the neat form of the compound. When dosed in rats and monkeys at 5 mg/kg, the SDD exhibited comparable exposure relative to the solution formulation. The SDD was also dosed in rats at 200 and 400 mg/kg and showed dose-proportional exposure compared to the solution formulation. Based on in vitro and in vivo data, the SDD formulation was selected for the toxicology study of BMS-B in rats. In summary, although the SDD approach could be quite challenging for highly lipophilic compounds because of the limitation on wetting and dissolution, the present study demonstrated that SDD can be applied in drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic poorly water-soluble compounds.

Lipophilic salts of poorly soluble compounds to enable high-dose lipidic SEDDS formulations in drug discovery

Graphical abstract Figure. No caption available. ABSTRACT Self‐emulsifying drug delivery systems (SEDDS) have been used to solubilize poorly water‐soluble drugs to improve exposure in high‐dose pharmacokinetic (PK) and toxicokinetic (TK) studies. However, the absorbable dose is often limited by drug solubility in the lipidic SEDDS vehicle. This study focuses on increasing solubility and drug loading of ionizable drugs in SEDDS vehicles using lipophilic counterions to prepare lipophilic salts of drugs. SEDDS formulations of two lipophilic salts—atazanavir‐2‐naphthalene sulfonic acid (ATV‐2‐NSA) and atazanavir‐dioctyl sulfosuccinic acid (ATV‐Doc)—were characterized and their performance compared to atazanavir (ATV) free base formulated as an aqueous crystalline suspension, an organic solution, and a SEDDS suspension, using in vitro, in vivo, and in silico methods. ATV‐2‐NSA exhibited ˜6‐fold increased solubility in a SEDDS vehicle, allowing emulsion dosing at 12 mg/mL. In rat PK studies at 60 mg/kg, the ATV‐2‐NSA SEDDS emulsion had comparable exposure to the free‐base solution, but with less variability, and had better exposure at high dose than aqueous suspensions of ATV free base. Trends in dose‐dependent exposure for various formulations were consistent with GastroPlus™ modeling. Results suggest use of lipophilic salts is a valuable approach for delivering poorly soluble compounds at high doses in Discovery.

Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311).

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.