Stephen Paul Collingwood

Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: quaternary amines.

We report the identification of a novel series of human epithelial sodium channel (ENaC) blockers that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride. Following a rational design hypothesis a series of quaternary amines were prepared and evaluated for their ability to block ion transport via ENaC in human bronchial epithelial cells (HBECs). Compound 11 has an IC(50) of 200nM and is efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED(50) of 44μgkg(-1) at 1h. As such, pyrazinoyl quaternary amines represent the first examples of a promising new class of human ENaC blockers.

8-Aryl xanthines potent inhibitors of phosphodiesterase 5.

In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.

Inhibition by viozan of extravasation induced in rat trachea by capsaicin is mediated exclusively by β2-adrenoceptors

Abstract. The mechanism by which 2(3H)-benzothiazolone, 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulphonyl]ethyl]amino]ethyl]-monohydrochloride (AR-C68397AA; viozan), a dual dopamine D2/β2-adrenoceptor agonist which has shown promise in the treatment of chronic obstructive pulmonary disease (COPD), inhibits the extravasation of plasma protein induced by capsaicin in the tracheas of Brown Norway rats has been re-evaluated.Viozan (10–30xa0µg/kg given intratracheally; i.t.) inhibited dose-dependently the extravasation of plasma protein tagged with Evans Blue into rat trachea induced by capsaicin (10xa0µg/kg i.t.). Similar effects were seen with the selective β2-adrenoceptor agonist, salbutamol (3–10xa0µg/kg i.t.), but the selective dopamine D2 receptor agonist, quinagolide (10–30xa0µg/kg i.t.), was inactive. The effects of viozan and salbutamol were abolished by propranolol (3xa0mg/kg) given intraperitoneally (i.p.) but unaffected by sulpiride (3xa0mg/kg i.p.).Thus, in contrast to claims in the literature, a functional response to dopamine D2 receptor activation in a preclinical model of oedema arising from sensory nerve fibre activation in the rat lung could not be demonstrated. Moreover, no qualitative difference could be demonstrated between the response to a dual D2/β2-adrenoceptor agonist and a selective β2-adrenoceptor agonist. The observations call into question whether a dual D2/β2-adrenoceptor agonist such as viozan would bring added benefit over established selective β2-adrenoceptor agonists in the therapy of COPD.

Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension.

A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.

Synthesis and duplex stability of oligodeoxyribonucleotides containing a 2′→5′-amide linkage

2′-Deoxy-2′-α-C-carboxymethyl-3′-O-tert-butyldimethylsilyl-5′-O-dimethoxytrityluridine (11a) and the corresponding 3′-deoxy derivative 2′,3′-dideoxy-2′-α-C-carboxymethyl-5′-O-dimethoxytrityluridine (11b) have been condensed with 5′-amino-5′-deoxythymidine to prepare dinucleotide analogues (5a and 5b) which contain a 2′→5′-amide linkage. These dimer units have been incorporated into deoxynucleotide dodecamers using solid-phase phosphoramidite chemistry. Thermal melting studies show that a single 2′→5′-amide linkage in a deoxyoligonucleotide has a considerable destabilising effect on duplexes formed with both the DNA and RNA complementary sequences. Interestingly, the amide linkage has a significantly greater destabilising influence in the DNA duplexes than in the RNA hybrids.