Thomas F. Walsh

A convergent synthesis of (S)-β-methyl-2-aryltryptamine based gonadotropin releasing hormone antagonists

Abstract A practical synthesis of (S)-β-methyl-2-aryltryptamine based gonadotropin releasing hormone antagonists which features a palladium-catalyzed Larock indole synthesis and a palladium-catalyzed Suzuki–Miyaura sequence to install the 2-position aryl substituent is reported.

Potent antagonists of gonadotropin releasing hormone receptors derived from quinolone-6-carboxamides

SAR studies which focused upon the C-6 position of a recently described series of quinolone gonadotropin releasing hormone antagonists are reported. Synthetic access to diverse quinolone-6-carboxamides was achieved via the palladium-catalyzed amino-carbonylation reactions of iodide 4 with various amines. Amides related to 9y were especially potent, functional antagonists of rat and human GnRH receptors.

Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor.

LH-21 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole) was previously reported as a neutral antagonist at the cannabinoid CB1 receptor which, despite its reported poor ability to penetrate into the brain, suppressed food intake and body weight in rats by intraperitoneal administration. In the present study, we studied the mechanism of action of LH-21 by characterizing its in vitro pharmacological properties and in vivo efficacy. LH-21 inhibited the binding of [3H]CP55940 to cloned human and rat CB1 receptors with IC50 values of 631+/-98 nM, and 690+/-41 nM, respectively, and acted as an inverse agonist in a cAMP functional assay using cultured cells expressing human, rat or mouse CB1 receptor. The compound was shown to be brain-penetrant in rats by intravenous administration. Importantly, a single dose of LH-21 (60 mg/kg, i.p.) caused a similar suppression of overnight food intake and body weight gain in wild-type and CB1 receptor knockout mice. Our results suggest that LH-21 is a low affinity inverse agonist for the CB1 receptor and does not act on the CB1 receptor to inhibit food intake in mice.

2-Arylindoles as gonadotropin releasing hormone (GnRH) antagonists: optimization of the tryptamine side chain

A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents.

Total syntheses of 6- and 7-azaindole derived GnRH antagonists

Abstract The palladium(0)-catalyzed heteroannulation of a triethylsilyl alkyne and an ortho -aminoiodopyridine derivative is used as the key step in a highly convergent route to 6- and 7-azaindoles of biological interest.

Quinolones as gonadotropin releasing hormone (GnRH) antagonists: simultaneous optimization of the C(3)-aryl and C(6)-substituents

A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal.

Potent dual antagonists of endothelin and angiotensin II receptors derived from α-phenoxyphenylacetic acids (Part III)

Abstract Screening a collection of α-phenoxyphenylacetic acid derived angiotensin II antagonists identified weak actives in an endothelin receptor binding assay. Synthetic modification of one of these leads has provided L-746,072 (13), a highly potent dual antagonist of angiotensin II and endothelin receptors.

Furo[2,3-b]pyridine-based cannabinoid-1 receptor inverse agonists: Synthesis and biological evaluation. Part 1

The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.

Shared determinants of receptor binding for subtype selective, and dual endothelin-angiotensin antagonists on the AT1 angiotensin II receptor

Site‐directed interspecies amino acid exchange was used to compare the binding determinants of a novel dual endothelial‐angiotensin receptor ligand, L‐746,072, with type‐1 angiotensin receptor (AT1) selective antagonists on AT receptors expressed in COS cells. These studies suggest that residues on AT receptors which are non‐conserved between amphibian and mammalian species play a greater role in subtype selective ligand recognition than for dual receptor ligands. These data also support the hypothesis that a common non‐peptide binding site exists within transmembrane domains on peptidergic receptors.

Chapter 10. Progress in the Development of Endothelin Receptor Antagonists

Publisher Summary This chapter discusses the highlights of recent progress in endothelin (ET) research and the advances in the development of nonpeptidic ET receptor antagonists. Recent research in ET has focused on the role of the ETs in the control of cardiovascular and renal function and their effects on the development of hypertension. The development of peptide agonists and antagonists of ET receptors is receiving attention. Recent availability of a variety of potent and selective ET receptor antagonists provides the opportunity to elucidate further, the role of ET in physiology as well as in pathophysiological states. ET receptors are differentiated by their relative affinities for the three peptide isoforms. A simplified classification has been taken into consideration, in which ET receptors are distinguished, by the order of their affinities. Distinct pattern of affinities has emerged. Receptors displaying these patterns of affinities have been classified as ET A , ET B , and ET C . The heterogeneity of ET receptor distribution in human coronary arteries and the predominance of ET B receptors in the human kidney further suggest that in at least some pathological states, blockade of both receptor subtypes may be essential to prevent the sequelae associated with elevated ET levels in human. The rapid progress in the identification of ET A -selective and ET A /ET B balanced antagonists suggests that the introduction of superior ET B -selective compounds and possibly endothelin converting enzyme (ECE) inhibitors is anticipated.