Thomas D. Gordon

Relationship between structure and bioavailability in a series of hydroxamate based metalloprotease inhibitors

Pharmacokinetic parameters for a series of C-terminally modified hydroxamate dipeptides were evaluated by in vitro and in vivo models. The presence of a tertiary base at the C-terminus significantly reduced biliary excretion and increased plasma half-life. Moreover, introduction of a thioether functionality produced a more favorable pharmacokinetic profile compared to the corresponding oxo- and aza-analogs.

An efficient synthesis and acylation of α-amino-β-keto-esters: Versatile intermediates in the synthesis of peptide mimetics.

Abstract A flexible and high yield synthesis of α-amino-β-keto esters has been developed via acylation of the ketimine derivatives of α-amino esters. These α-amino-β-keto-esters were acylated with chiral amino acid derivatives in 36–95% yields.

Synthesis of substituted imidazopyrazines as ligands for the human somatostatin receptor subtype 5

A new preparation of trisubstituted imidazopyrazines and dihydroimidazopyrazines via parallel synthesis using aminoacids and bromoketones resulted in the discovery of non-peptidic sst5 selective agonists.

Peptide azoles: A new class of biologically-active dipeptide mmetics.

Abstract Appropriately substituted thiazoles, imidazoles and oxazoles have been designed to be useful mimetics of dipeptide moieties. These “peptide azoles” have been shown to be potent antagonists of substances P as measured by isolated tissue assays such as the isolated guinea-pig ileum. A novel, chiral synthesis of these peptide azoles from aminoacids has been developed.

Scalable Synthesis and Isolation of the Four Stereoisomers of Methyl 1-Amino-3-(4-bromophenyl)cyclopentanecarboxylate, Useful Intermediates for the Synthesis of S1P1 Receptor Agonists

The individual isomers of methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate are useful intermediates for the synthesis of S1P1 receptor agonists. Herein we describe a scalable synthesis and isolation of each of the four stereoisomers of this compound in gram quantities with >98% ee and de. The utility of this approach is demonstrated by the synthesis of ((1R,3R)-1-amino-3-(4-octylphenyl)cyclopentyl)methanol in 7 steps, 11% overall yield, and >98% ee and de.

Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of human farnesyltransferase, BIM‐46228

Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a wide spectrum of human cancers (pancreas, thyroid, colon, non‐small‐cell lung cancer). Membrane anchorage of Ras, required for functional activity in signal transduction, is facilitated by post‐translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C‐terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel FTase inhibitor, BIM‐46228, which showed (i) specific inhibition of purified human FTase enzyme, (ii) inhibition of proliferation in vitro in a large spectrum of human tumor cell lines, (iii) inhibition of growth of human tumor xenografts in athymic nude mice treated by per os administration and (iv) the benefits of in vitro combination of its activity with chemotherapy or radiotherapy.

Discovery of thieno[2,3-c]pyridines as potent COT inhibitors

Evaluation of hit chemotypes from high throughput screening identified a novel series of 2,4-disubstituted thieno[2,3-c]pyridines as COT kinase inhibitors. Structural modifications exploring SAR at the 2- and 4-positions resulting in inhibitors with improved enzyme potency and cellular activity are disclosed.

Identification of a selective thieno[2,3-c]pyridine inhibitor of COT kinase and TNF-α production

COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.

Novel non-peptide ligands for the somatostatin sst3 receptor.

A series of imidazole derivatives has been prepared using high throughput parallel synthesis. Several compounds showed high affinity (Ki in 10(-6)-10(-8) M range) and selectivity at recombinant human somatostatin receptor subtype 3 (hsst3).

Cyclic Peptides Related to Somatostatin Containing a Novel Imidazole Derived cis-Amide Mimetic

The design of structural fragments that mimic specific aspects of peptide secondary structure is a continuing challenge to medicinal chemists. We wish to describe a novel approach to cis amide mimicry employing an extension of our “peptide azole” concept [1] (1). We now demonstrate that this concept can be extended to mimic a cis amide bond (2), by modifying the substitution pattern of the imidazole. These cis amide mimics can be readily assembled by alkylation of a protected 2-(aminomethyl) imidazole with bromoacetate.