Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.

Solid state characterization of mometasone furoate anhydrous and monohydrate forms.

Mometasone furoate is a potent glucocorticoid anti-inflammatory agent. Its anhydrous Form 1 and monohydrate form were characterized by X-ray crystallography, X-ray powder diffraction at ambient and elevated temperature, thermal analysis, FT-IR, and dynamic moisture adsorption. In Form 1, mometasone furoate molecules pack tightly with molecules interlocked in a space group of P2(1)2(1)2(1). The monohydrate form crystallizes in space group P1. The unit cell of the monohydrate contains one water molecule and one mometasone furoate molecule. The water molecules form channels along the a axis and mometasone furoate molecules pack in layers in the same direction. Dehydration was observed between 60 and 100 degrees C by thermogravimetric analysis with a heating rate of 10 degrees C/min. It corresponds to a broad endotherm over the same temperature range in the differential scanning calorimetry with the same heating rate. Variable temperature X-ray powder diffraction reveals that a new anhydrous form (Form 2) was fully produced above 90 degrees C. This crystalline form was converted to Form 1 after being heated above 150 degrees C; and was totally converted to the monohydrate after 1 day at 23 degrees C, 45% RH.

Design, synthesis, structure-function relationship, bioconversion, and pharmacokinetic evaluation of ertapenem prodrugs.

Described here are synthesis and biological evaluations of diversified groups of over 57 ertapenem prodrugs which include alkyl, methylenedioxy, carbonate, cyclic carbonate, carbamate esters, and esters containing active transport groups (e.g., carboxyl, amino acid, fatty acids, cholesterol) and macrocyclic lactones linking the two carboxyl groups. Many of the prodrugs were rapidly hydrolyzed in rat plasma but not in human plasma and were stable in simulated gastrointestinal fluid. The diethyl ester prodrug showed the best total absorption (>30%) by intredeudenal dosing in dogs, which could potentially be improved by formulation development. However, its slow rate of the hydrolysis to ertapenem also led to the presence of large amounts of circulating monoester metabolites, which pose significant development challenges. This study also suggests that the size of susbtituents at C-2 of carbapenem (e.g., benzoic acid of ertapenem) has significant impact on the absorption and the hydrolysis of the prodrugs.

Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad spectrum antibacterial agents.

Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC50 > 18 µM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC50 = 1.02 µM) and topo IV (IC50 = 10.4 µM). AM8191 showed parenteral and oral efficacy (ED50) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.

The discovery of N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822): a potent and selective glucagon receptor antagonist.

A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice.

Design, synthesis, and evaluation of prodrugs of ertapenem.

Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.

Exploratory drug safety: a discovery strategy to reduce attrition in development.

Identification of novel new molecules which hold the greatest promise of safe and effective therapies remains a continuous challenge to the pharmaceutical industry. This has led the industry to implement strategies for identification of the most promising candidates during the discovery phase and for their safe and expeditious advancement through development. Testing for potential liable properties in the discovery phase has included the evaluation of major areas of pharmaceutics that have led to failure such as its physical and pharmaceutical properties, drug metabolism and pharmacokinetic characteristics, various safety endpoints including pre-development safety pharmacology, general toxicology and genetic toxicology and interrogation of counter-screen data to identify off-target affinities (i.e., receptors, ion channels, transporters, kinases, etc.) that pose a concern. Amongst the many important areas of concern is the potential for toxicities of the major organ systems. To mitigate this concern, a strategy pursued is to identify the prominent toxicological properties of the candidate prior to its recommendation for development. The results of these studies in discovery allow exclusion of the candidate before the expenditure of resources and time typical of development. In addition, the discovery phase toxicology studies serve to address key questions that may have arisen from the study of another molecule, the phenotypic profile from pre-clinical models where the therapeutic target has been genetically modified or concerns that have been raised as a result of other investigations. Importantly, the results of the exploratory drug safety studies will be used by the sponsor to judge the potential risks associated with continued pursuit of a potential development candidate. In many ways, pre-clinical toxicological investigations in discovery serve the important objective of identifying the most promising candidates to progress into development and onto registration.