Anthony Howard Ingall

FPL 66096: a novel, highly potent and selective antagonist at human platelet P2T-purinoceptors.

1 ADP‐dependent platelet aggregation is mediated by the P2T‐purinoceptor and is specifically inhibited by ATP, which is a competitive P2T‐purinoceptor antagonist. However, ATP functions as an agonist at other P2‐purinoceptor subtypes in other tissues and is, therefore, non‐selective. This paper describes the effects of the novel ATP analogue, FPL 66096 (2‐propylthio‐D‐β,γ‐difluoromethylene ATP), on ADP‐induced and ADP‐independent aggregation of human washed platelets and in standard preparations containing P2X‐ (rabbit ear artery) and P2Y‐purinoceptors (guinea‐pig aorta). 2 In suspensions of human washed platelets, FPL 66096 (1‐100nM) produced concentration‐dependent rightward displacement of concentration‐effect (E/[A]) curves obtained for ADP‐induced platelet aggregation. Logistic fitting of E/[A] data indicated that the effect of FPL 66096 was consistent with simple competition with a pKB value of 8.66. FPL 66096 (10–1000 nm) had no effect on aggregation produced by the thromboxane A2‐mimetic, U46619 (0.1–10 μm) when the response to this agent was rendered ADP‐independent by inclusion of the non‐selective P2‐purinoceptor antagonist, suramin (100 μ). 3 The antiaggregatory potency of FPL 66096 was not influenced by increasing the incubation time from 2 to 15min nor by inclusion of the P1‐purinoceptor antagonist 8‐sulphophenyltheophylline at a concentration (300 μm) that produced a 68 fold rightward displacement of the anti‐aggregatory E/[A] curve for the P1‐purinoceptor agonist, 5′‐N‐ethylcarboxamidoadenosine (0.1–1000 μm). 4 FLP 66096 behaved as a weak (pA50 3.68) but full P2x‐purinoceptor agonist in preparations of the rabbit isolated ear artery and as a weak, competitive antagonist (apparent pKB 4.71) at P2Y‐purinoceptors in the guinea‐pig isolated aorta, indicating a selectivity of at least 9000 fold for the P2T‐subtype. In the latter preparation, non‐specific relaxations were produced by concentrations of FPL 66096 ≥ 10 μm. 5 These results indicate that FPL 66096 is a P2T‐purinoceptor antagonist of unprecedented potency and selectivity and that its effects are consistent with simple competition at the P2T‐purinoceptor. Therefore, FPL 66096 represents a novel pharmacological tool in the classification of P2‐purinoceptors and in the elucidation of the mechanisms involved in activation of platelets by ADP.

The medicinal chemistry of the P2 receptor family.

Publisher Summary This chapter reviews that the purinoreceptors are a family of receptors that are activated by nucleosides and nucleotides. The purinoreceptors is divided into two families: The P 1 receptors, where nucleosides are more active than nucleotides and the P 2 receptors, where nucleotides are more active than nucleosides. The chapter concentrate on the medicinal chemistry of the P 2 receptor family. It also reviews the P 2 receptor is divided into two major classes, P2X and P2Y. The P2X receptors belong to the ligand-gated cation channel family; whereas the P2Y receptors are members of the seven transmembrane G-protein coupled receptor family. P2X and P2Y receptors are numbered sequentially according to the clone being reported. Capital letters are used to denote functional mammalian receptors or their non-mammalian homologues. Lower case is used to denote orphan mammalian receptors such as receptors having P 2 sequence homology, but no identified functional response and functional non-mammalian receptors with no known mammalian homologue. This system has led to non-sequential numbering of confirmed mammalian P 2 receptors and may necessitate further revision of nomenclature for this class of receptors.

Design driven HtL: The discovery and synthesis of new high efficacy β2-agonists

The design and synthesis of a new series of high efficacy β(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious β(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of β(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.

Design-driven LO: The discovery of new ultra long acting dibasic β2-adrenoceptor agonists

Starting with the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full β(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.

Discovery of AZD3199, An Inhaled Ultralong Acting β2 Receptor Agonist with Rapid Onset of Action.

A series of dibasic des-hydroxy β2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human β-adrenoreceptors demonstrated a series of highly potent and selective β2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled β2 receptor agonist with rapid onset of action.

Novel cobalt complex inhibitors of mitochondrial calcium uptake.

Reperfusion of the ischaemic myocardium leads to intracellular calcium overload followed by mitochondrial dysfunction, resulting in insufficient energy supply and ultimately myocardial necrosis. Ruthenium red (RR), a potent mitochondrial calcium uptake inhibitor, prevents this disruption to mitochondrial metabolism and improves post reperfusion recovery. This therefore suggested that mitochondrial calcium influx is an attractive target for the treatment of reperfusion injury. However, RR is unsuitable for therapeutic use, so we undertook a search for novel compounds which inhibit mitochondrial calcium uptake. The most potent compounds discovered were simple tris(ethylenediamine) transition metal complexes and dinuclear Co complexes. The structure-activity relationship (SAR) of these small molecules has helped to define the structural requirements for inhibition of calcium transport by outlining the size and charge dependency of the interactive site on the mitochondrial calcium uniporter.

Synthesis of (1R,2S,3R,4R)-2,3,4-trihydroxycyclopentylamine from D-ribonolactone

A seven-step procedure for the transformation of ribonolactone 3 into the aminotriol 12 can be effected in 28% overall yield.