Prostanoid receptor antagonists: development strategies and therapeutic applications

Abstract

Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP(1), EP(2) ...) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP(1), TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP(2)). While some antagonists are structurally related to the natural agonist, most recent compounds are 'non-prostanoid' (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD(2) (acting on DP(1) and DP(2) receptors) and PGE(2) (on EP(1) and EP(4) receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage.

Figure 1

DP₁ receptor antagonists. The natural ligand PGD₂ is shown in the box; the trans-orientation of the α (upper) and ω (lower) side-chains and (S) configuration at C15 are found in primary products of all COX/synthase systems. BW-A868C and ZK-138357 are each composed of four diastereoisomers (chiral centres at C8/C15 and C10/C15 respectively); compound 1 is racemic. Indomethacin is a lead compound for the non-prostanoid antagonists shown in the lower row; N-benzoyl-2-methyl-indol-3-yl-acetic acid templates are shown in red. The 3(S)-enantiomer of MK-0524 has 320-fold lower affinity for the human DP₁ receptor (Sturino et al., 2007).

Figure 8

TP receptor antagonists. Conversion of PGH₂ to TXA₂ by thromboxane synthase (TXS) is shown in the box; α and ω represent natural 2-series side-chains. The pinane-thromboxane residue (related to 1(S)-α-pinene) is shown in blue; the 6-oxabicyclo(2.2.1)heptane system is in red. AH-23848 has the same α- and ω-chains as GR-32191. Benzenesulphonamide residues present in both prostanoid and non-prostanoid antagonists are shown in cerise. TP antagonists with two types of additional activity are presented. (A) IP agonism is conferred by the diphenylmethyl-heteroatomic unit in the bicyclo[2.2.2]octene analogue EP-157. (B) TXS inhibitory activity is conferred by the pyridin-3-yl residue (green) in isbogrel and ZD-1542 and by a similar replacement for ring A in relatives of GR-32191 (e.g. GR-83783; see text). Additionally, the broken arrows (lower right) typically indicate attachment of part of a TP antagonist to isbogrel (or ridogrel) to generate novel combined TP antagonist/TXS inhibitors; the tether (0–11 carbon units) has also been attached to the left-hand phenyl ring of ICI-192605 (2–8 carbon units) (Ackerley et al., 1995).

Figure 2

DP₂ receptor antagonists. Inverted 2-methyl-indole-acetic acid residues (compare with 6) are highlighted in red; ramatroban has an extra methylene (C2a). The phenylacetic acid moiety is shown in blue in fenclofenac, a lead molecule for compound 11. Compound 12, K-117 and K-604 contain a tetrahydroquinoline residue (green).

Figure 3

EP₁ receptor antagonists. The natural ligand PGE₂ is shown in the box. The dibenzoxazepine residue in SC-51322 is shown in blue. Aryl-sulphonamido residues in antagonists with prostanoid and non-prostanoid structures are shown in cerise; ONO-NT-012 contains a styryl-sulphonamido moiety. The 1,2-biaryl-cyclopentene pharmacophores in GW-848687 and MF-266-1 are shown in red. Ring A in GW-848687 is part of a picolinic acid (pyridine-2-carboxylic acid) residue.

Figure 4

EP₃ receptor antagonists. The AT₁ receptor antagonist, compound 16, is a lead molecule for the biaryl-ene-acyl-sulphonamide antagonists (pharmacophore in red). The left-hand portion of this pharmacophore corresponds to the cinnamic acid moiety in compounds 18 and 19 (see broken brackets). L-826266 is a chloro analogue of L-798106. The lower-middle brackets show modifications to the indole nucleus in the EP₃ antagonist series of DeCode Genetics.

Figure 5

EP₄ receptor antagonists. L-161982 is a methyl analogue of compound 16 in Figure 4. Acyl-sulphonamido residues are shown in red. The bonds indicated by asterisks in MF-498 are subject to oxidative/hydrolytic attack in vivo; the corresponding substituents in compound 20 prevent these transformations.

Figure 6

FP receptor and prostamide receptor antagonists. The natural ligand PGF_2α and its 1-ethanolamide derivative, prostamide F_2α, are shown in the box. AL-3138 and AL-8810 are FP partial agonists in many systems; α= corresponding side-chain in PGF_2α. The THG analogues are peptides: amide (CO-NH) residues are shown as red bars. The AGN analogues (upper right) are prostamide receptor antagonists; C1-amide residues are shown in blue.

Figure 7

IP receptor antagonists. The natural ligand PGI₂ (prostacyclin) is shown in the box. 2-(Phenylamino)-imidazoline moieties are shown in blue and phenylalanine residues in red (S-configuration in compound 24). RO-3244794 is a difluoro analogue of RO-3244019.