Kevin Stefanski

Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily

Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.

Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations

Supersaturatable cosolvent (S‐cosolvent) and supersaturatable self‐emulsifying drug delivery systems (S‐SEDDS) are designed to incorporate water soluble cellulosic polymers such as hydroxypropyl methylcellulose (HPMC), which may inhibit or retard drug precipitation in vivo. A poorly soluble drug, PNU‐91325, was used as a model drug in this study to illustrate this formulation approach. The comparative in vitro studies indicated that the presence of a small amount HPMC in the formulation was critical to achieve a stabilized supersaturated state of PNU‐91325 upon mixing with water. An in vivo study was conducted in dogs for assessment of the oral bioavailability of four formulations of PNU‐91325. A five‐fold higher bioavailability (∼ 60%) was observed from a S‐cosolvent formulation containing propylene glycol (PG) + 20 mg/g HPMC as compared to that (∼ 12%) of a neat polyethylene glycol (PEG) 400 formulation. The low bioavailability of the PEG 400 formulation is attributed to the uncontrolled precipitation of PNU‐91325 upon dosing, a commonly observed phenomenon with the cosolvent approach. A S‐SEDDS formulation composed of 30% w/w Cremophor (surfactant), 9% PEG 400, 5% DMA, 18% Pluronic L44, 20% HPMC, and other minor components showed an oral bioavailability of ∼ 76%, comparable to that of a neat tween formulation (bioavailability: ∼ 68%). The significant improvement of the oral bioavailability of the supersaturatable S‐cosolvent and S‐SEDDS formulations is attributed to a high free drug concentration in vivo as a result of the generation and stabilization of the supersaturated state due to the incorporation of polymeric precipitation inhibitor.

Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development.

This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.

Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions.

The in vitro dissolution mechanism of an amorphous solid dispersion (ASD) remains elusive and highly individualized, yet rational design of ASDs with optimal performance and prediction of their in vitro/in vivo performance are very much desirable in the pharmaceutical industry. To this end, we carried out comprehensive investigation of various ASD systems of griseofulvin, felodipine, and ketoconazole, in PVP-VA or HPMC-AS at different drug loading. Physiochemical properties and processes related to drug-polymer-water interaction, including the drug crystallization tendency in aqueous medium, drug-polymer interaction before and after moisture exposure, supersaturation of drug in the presence of polymer, polymer dissolution kinetics, etc., were characterized and correlated with the dissolution performance of ASDs at different dose and different drug/polymer ratio. It was observed that ketoconazole/HPMC-AS ASD outperformed all other ASDs in various dissolution conditions, which was attributed to the drugs low crystallization tendency, the strong ketoconazole/HPMC-AS interaction and the robustness of this interaction against water disruption, the dissolution rate and the availability of HPMC-AS in solution, and the ability of HPMC-AS in maintaining ketoconazole supersaturation. It was demonstrated that all these properties have implications for the dissolution performance of various ASD systems, and further quantification of them could be used as potential predictors for in vitro dissolution of ASDs. For all ASDs investigated, HPMC-AS systems performed better than, or at least comparably with, their PVP-VA counterparts, regardless of the drug loading or dose. This observation cannot be solely attributed to the ability of HPMC-AS in maintaining drug supersaturation. We also conclude that, for fast crystallizers without strong drug-polymer interaction, the only feasible option to improve dissolution might be to lower the dose and the drug loading in the ASD. In this study, we implemented an ASD/water Flory-Huggins parameter plot, which might assist in revealing the physical nature of the drug-polymer interaction. We also introduced supersaturation parameter and dissolution performance parameter as two quantitative measurements to compare the abilities of polymers in maintaining drug supersaturation, and the dissolution performance of various solid dispersions, respectively.

Initial Drug Dissolution from Amorphous Solid Dispersions Controlled by Polymer Dissolution and Drug-Polymer Interaction

AbstractPurposeTo identify the key formulation factors controlling the initial drug and polymer dissolution rates from an amorphous solid dispersion (ASD).MethodsKetoconazole (KTZ) ASDs using PVP, PVP-VA, HMPC, or HPMC-AS as polymeric matrix were prepared. For each drug-polymer system, two types of formulations with the same composition were prepared: 1. Spray dried dispersion (SDD) that is homogenous at molecular level, 2. Physical blend of SDD (80% drug loading) and pure polymer (SDD-PB) that is homogenous only at powder level. Flory-Huggins interaction parameters (χ) between KTZ and the four polymers were obtained by Flory-Huggins model fitting. Solution 13C NMR and FT-IR were conducted to investigate the specific drug-polymer interaction in the solution and solid state, respectively. Intrinsic dissolution of both the drug and the polymer from ASDs were studied using a Higuchi style intrinsic dissolution apparatus. PXRD and confocal Raman microscopy were used to confirm the absence of drug crystallinity on the tablet surface before and after dissolution study.ResultsIn solid state, KTZ is completely miscible with PVP, PVP-VA, or HPMC-AS, demonstrated by the negative χ values of −0.36, −0.46, −1.68, respectively; while is poorly miscible with HPMC shown by a positive χ value of 0.23. According to solution 13C NMR and FT-IR studies, KTZ interacts with HPMC-AS strongly through H-bonding and dipole induced interaction; with PVPs and PVP-VA moderately through dipole-induced interactions; and with HPMC weakly without detectable attractive interaction. Furthermore, the “apparent” strength of drug-polymer interaction, measured by the extent of peak shift on NMR or FT-IR spectra, increases with the increasing number of interacting drug-polymer pairs. For ASDs with the presence of considerable drug-polymer interactions, such as KTZ/PVPs, KTZ/PVP-VA, or KTZ /HPMC-AS systems, drug released at the same rate as the polymer when intimate drug-polymer mixing was ensured (i.e., the SDD systems); while drug released much slower than the polymer when molecular level mixing or drug-polymer interaction was absent (SDD-PB systems). For ASDs without drug-polymer interaction (i.e., KTZ/HPMC systems), the mixing homogeneity had little impact on the release rate of either the drug or the polymer thus SDD and SDD-PB demonstrated the same drug or polymer release rate, while the drug released slowly and independently of polymer release.ConclusionsThe initial drug release from an ASD was controlled by 1) the polymer release rate; 2) the strength of drug-polymer interaction, including the intrinsic interaction caused by the chemistry of the drug and the polymer (measured by the χ value), as well as that the apparent interaction caused by the drug-polymer ratio (measure by the extent of peak shift on spectroscopic analysis); and 3) the level of mixing homogeneity between the drug and polymer. In summary, the selection of polymer, drug-polymer ratio, and ASD processing conditions have profound impacts on the dissolution behavior of ASDs. Graphical AbstractRelationship between initial drug and polymer dissolution rates from amorphous solid dispersions with different mixing uniformity and drug-polymer interactions

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.

Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kδ inhibitors.

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.

Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.

Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and Its Impact on Dissolution Performance

Amorphous phase separation (APS) is commonly observed in amorphous solid dispersions (ASD) when exposed to moisture. The objective of this study was to investigate: (1) the phase behavior of amorphous solid dispersions composed of a poorly water-soluble drug with extremely low crystallization propensity, BMS-817399, and PVP, following exposure to different relative humidity (RH), and (2) the impact of phase separation on the intrinsic dissolution rate of amorphous solid dispersion. Drug-polymer interaction was confirmed in ASDs at different drug loading using infrared (IR) spectroscopy and water vapor sorption analysis. It was found that the drug-polymer interaction could persist at low RH (≤75% RH) but was disrupted after exposure to high RH, with the advent of phase separation. Surface morphology and composition of 40/60 ASD at micro-/nano-scale before and after exposure to 95% RH were also compared. It was found that hydrophobic drug enriched on the surface of ASD after APS. However, for the 40/60 ASD system, the intrinsic dissolution rate of amorphous drug was hardly affected by the phase behavior of ASD, which may be partially attributed to the low crystallization tendency of amorphous BMS-817399 and enriched drug amount on the surface of ASD. Intrinsic dissolution rate of PVP decreased resulting from APS, leading to a lower concentration in the dissolution medium, but supersaturation maintenance was not anticipated to be altered after phase separation due to the limited ability of PVP to inhibit drug precipitation and prolong the supersaturation of drug in solution. This study indicated that for compounds with low crystallization propensity and high hydrophobicity, the risk of moisture-induced APS is high but such phase separation may not have profound impact on the drug dissolution performance of ASDs. Therefore, application of ASD technology on slow crystallizers could incur low risks not only in physical stability but also in dissolution performance.