N-Arylsulfonyl-α-amino carboxamides are potent and selective inhibitors of the chemokine receptor CCR10 that show efficacy in the murine DNFB model of contact hypersensitivity.

Compound 1 ((4-amino-3,5-dichlorophenyl)-1-(4-methylpiperidin-1-yl)-4-(2-nitroimidazol-1-yl)-1-oxobutane-2-sulfonamido) was discovered to be a 690nM antagonist of human CCR10 Ca flux. Optimization delivered (2R)-4-(2-cyanopyrrol-1-yl)-S-(1H-indol-4-yl)-1-(4-methylpiperidin-1-yl)-1-oxobutane-2-sulfonamido (eut-22) that is 300 fold more potent a CCR10 antagonist than 1 and eliminates potential toxicity, mutagenicity, and drug-drug-interaction liabilities often associated with nitroaryls and anilines. eut-22 is highly selective over other GPCR's, including a number of other chemokine receptors.

Rapid synthesis of an array of trisubstituted urea-based soluble epoxide hydrolase inhibitors facilitated by a novel solid-phase method.

A 270-membered library of trisubstituted ureas was synthesized and evaluated for inhibition of soluble epoxide hydrolase. Library design and reagent selection was guided by the use of a pharmacophore model and synthesis of the array was enabled with a general solid-phase method. This array approach facilitated multi-dimensional SAR around this series and identified functionality responsible for binding affinity, as well as opportunities for modulating the overall in vitro profiles of this class of soluble epoxide hydrolase inhibitors.

5-Aminomethylbenzimidazoles as potent ITK antagonists.

Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described.

Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors.

Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency.

Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase.

Histone lysine methylation has important roles in the organization of chromatin domains and the regulation of gene expression. To analyze its function and modulate its activity, we screened for specific inhibitors against histone lysine methyltransferases (HMTases) using recombinant G9a as the target enzyme. From a chemical library comprising 125,000 preselected compounds, seven hits were identified.

Solid-phase total synthesis and structure proof of callipeltin B.

The cytotoxic, cyclic heptadepsipeptide, natural product callipeltin B was synthesized on a solid-phase support in 15% overall yield. Comparison of the 1H NMR spectra of three synthetic isomers with those of callipeltin B confirmed the configurational reassignment of its threonine residues as d-allothreonine and the assignment of the configuration of its beta-methoxytyrosine residue as (2R,3R).

Diverse 2-carboxamide-3-amino-substituted quinoxalines: synthesis and reactivity investigation for library generation.

Described herein is the development of a robust synthetic route applicable to parallel synthesis of diverse 2-carboxamide-3-amino-substituted quinoxalines. In addition to the scope and limitations of the methods developed, a purification strategy employing solid-phase extraction (SPE) and application of the methods to a small parallel array of compounds are discussed.

Facile incorporation of urea pseudopeptides into protease substrate analogue inhibitors.

A new procedure that employs a one-pot, oxidative Hofmann rearrangement to incorporate a urea linkage into peptide backbones is detailed herein. This methodology was used to replace the scissile peptide bonds of [Leu5]enkephalin and a hexapeptide HIV-1 protease substrate. The [Leu5]enkephalin analogue was found to inhibit cleavage of hippurylhistidylleucine (HHL) by porcine kidney angiotensin-converting enzyme (PK-ACE) with a 0.

NMR solution structure of the isolated Apo Pin1 WW domain: comparison to the x-ray crystal structures of Pin1.

The NMR solution structure of the isolated Apo Pin1 WW domain (6-39) reveals that it adopts a twisted three-stranded antiparallel beta-sheet conformation, very similar to the structure exhibited by the crystal of this domain in the context of the two domain Pin1 protein. While the B factors in the apo x-ray crystal structure indicate that loop 1 and loop 2 are conformationally well defined, the solution NMR data suggest that loop 1 is quite flexible, at least in the absence of the ligand. The NMR chemical shift and nuclear Overhauser effect pattern exhibited by the 6-39 Pin1 WW domain has proven to be diagnostic for demonstrating that single site variants of this domain adopt a normally folded structure.