Cheryl A. Grice

Tricyclic aminopyrimidine histamine H4 receptor antagonists

This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.

Discovery of a novel series of selective HCN1 blockers.

The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.

Indole- and benzothiophene-based histamine H3 antagonists.

Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.

Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors: part 1.

A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.

Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors. Part 2: Modification of P3, P4, and P5 regions

A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4-fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution.

Current status of leukotriene A4 hydrolase inhibitors

Background: Leukotriene A4 hydrolase (LTA4H) is a ubiquitously distributed 69-kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA4H stereospecifically catalyzes the transformation of the unstable epoxide LTA4 to the diol leukotriene B4 (LTB4), a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, T cells, dendritic cells, smooth muscle cells and keratinocytes. Inhibiting the formation of LTB4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease, asthma and atherosclerosis. Objective: The focus of this review will be on patent applications/patents containing LTA4H inhibitors that were published between 1996 and March 2008 from four different companies. The documents reviewed are presented in a tabular manner. Method: The first part of this review focuses on the primary literature supporting LTA4H as a potential target. The second part covers the patent literature organized by applicant identified during the prescribed period. Conclusion: Activity towards identifying small molecule inhibitors of LTA4H has escalated in the last few years in line with important scientific and clinical developments involving the leukotriene pathway. One inhibitor from deCODE, DG-051, is reported to be in clinical trials for myocardial infarction and future reports of clinical efficacy will undoubtedly stimulate further work in the field by others.

Thioether acetamides as P3 binding elements for tetrahydropyrido-pyrazole cathepsin S inhibitors

A series of tetrahydropyrido-pyrazole cathepsin S (CatS) inhibitors with thioether acetamide functional groups were prepared with the goal of improving upon the cellular activity of amidoethylthioethers. This Letter describes altered amide connectivity, in conjunction with changes to other binding elements, resulting in improved potency, as well as increased knowledge of the relationship between this chemotype and human CatS activity.

Practical Segregation of Incompatible Reagents in the Organic Chemistry Laboratory

A new protocol of incompatible chemical reagent segregation has been developed. Serving as a second-level segregation beyond typical first-level separation of explosives/nonexplosives, flammables/nonflammables, corrosives/noncorrosives, and caustics/noncaustics, this method involves assigning the reactive functional groups constituting a given reagent to one of seven classes based on reactivity and then storing that reagent according to which of those functional groups is of the highest priority, based on defined rankings. This scheme, requiring a small number of segregation groups, differs from previously reported segregation methods by accounting for the fact that organic reagents typically contain multiple sites of varying reactivity.