David Timothy Macpherson

GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility.

Abstract  There is an urgent clinical need for a safe, efficacious stimulant of gastric emptying; current therapies include erythromycin (an antibiotic with additional properties which preclude chronic use) and metoclopramide (a 5‐hydroxytryptamine type 4 receptor agonist and an antagonist at brain D2 receptors, associated with movement disorders). To move away from the complex motilide structure of erythromycin, a small molecule motilin receptor agonist, GSK962040, was identified and characterized. The compound was evaluated using recombinant human receptors, rabbit and human isolated stomach preparations known to respond to motilin and in vivo, by measuring its ability to increase defecation in conscious rabbits. At the human motilin receptor, the pEC50 (the negative logarithm to base 10 of the EC50 value, the concentration of agonist that produces 50% of the maximal response) values for GSK962040 and erythromycin as agonists were, respectively, 7.9 and 7.3; GSK962040 had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L−1–10 μmol L−1 caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 ± 47% at 3 μmol L−1. In human‐isolated stomach, GSK962040 10 μmol L−1, erythromycin 10 μmol L−1 and [Nle13]‐motilin 100 nmol L−1, each caused muscle contraction of similar amplitude. In conscious rabbits, intravenous doses of 5 mg kg−1 GSK962040 or 10 mg kg−1 erythromycin significantly increased faecal output over a 2‐h period. Together, these data show that GSK962040, a non‐motilide structure, selectively activates the motilin receptor. Simplification of the structural requirements to activate this receptor greatly facilitates the design of potentially new medicines for gastroparesis.

Bace-1 Inhibitors Part 3: Identification of Hydroxy Ethylamines (Heas) with Nanomolar Potency in Cells.

This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.

BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs).

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimers disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.

Pictet–Spengler/Palladium Catalyzed Allenylation and Carbonylation Processes

Abstract The tactical combination of the Pictet–Spengler reaction with Pd catalyzed reactions with allene and with carbon monoxide provides rapid access to a range of tetrahydro-β-carboline and tetrahydroisoquinoline derivatives via intramolecular trapping of intermediate π-allyl– and acyl–palladium(II) complexes by the indolic or secondary amino moieties generating fused azepine and δ-lactam derivatives. Chiral tryptophan examples are also described.

Solid phase sequential 1,3-dipolar cycloaddition–Pictet–Spengler reactions

Abstract Up to six bonds and two rings can be created, in five component processes (five points of diversity), by AgOAc catalysed imine cycloaddition to Wang resin acrylate followed by Pictet–Spengler and Pd(0) catalysed reactions.

Discovery of N-(3-Fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine (GSK962040), the First Small Molecule Motilin Receptor Agonist Clinical Candidate

N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.

Sequential 1,3-Dipolar Cycloaddition-Pictet–Spengler Reactions. A Versatile Tactical Combination

Abstract The combination of thermal or Ag(I) catalysed imine→azomethine ylide→cycloaddition cascades with a subsequent Pictet–Spengler reaction allows the assembly of polyfunctional N-heterocycles, via formation of 4 bonds and 2 rings, in good yield.

On the utility of S-mesitylsulfinimines for the stereoselective synthesis of chiral amines and aziridines

The synthetic utility of S-mesitylsulfinimines for the synthesis of chiral amines and aziridines was examined through their reactions with Grignard reagents, with the ylides derived from trimethylsulfonium iodide and S-allyl-tetrahydrothiophenium bromide and through an aza-Darzens manifold, affording convenient access to a diverse range of highly substituted chiral amines and aziridines in high yields and excellent stereoselectivities.

Conjugate addition to the ethylene ketal of 2-carbomethoxy-2-cyclopentenone a synthesis of sarkomycin

Abstract 1,4-addition of nitronate anions to the title ketal ester (III) is described; one of the adducts is converted to sarkomycin.

The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor

Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.