Methoxytetrahydropyrans. A new series of selective and orally potent 5-lipoxygenase inhibitors.

Investigation of the SAR of the lead (methoxyalkyl)thiazole 1-[3-(naphth-2-ylmethoxy)phenyl]-1-thiazol-2-ylprop yl methyl ether (1, ICI 211965) led to the methoxytetrahydropyrans, a new series of 5-lipoxygenase (5-LPO) inhibitors exemplified by the parent compound 4-[3-(naphth-2-ylmethoxy)phenyl]-4- methoxy-3,4,5,6-tetrahydro-2H-pyran (4f). In vitro 4f inhibited leukotriene C4 (LTC4) synthesis in zymosan-stimulated plasma-free mouse macrophages and LTB4 synthesis in A-23187-stimulated human whole blood (IC50s 0.5 nM and 0.07 microM, respectively). In the rat 4f inhibited LTB4 synthesis in blood ex vivo and in zymosan-inflamed air pouch exudate with an ED50 3 h after oral dosing of 10 mg/kg in each system. In seeking more potent orally active compounds, strategies were explored in congeners of 4f for reducing lipophilicity without sacrificing potency. For example, replacement of 2-naphthyl of 4f by various aza- and oxoheterocycles afforded compounds in which log P is reduced by 1.7-2.3 units while potency in human whole blood in vitro was maintained or enhanced relative to 4f. In addition, the oxoheterocyclic replacements provided compounds with improved oral potency and the preferred compound from this group is 6-[[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4- yl)phenoxy]methyl]-1-methylquinol-2-one (4y). In the in vitro systems, 4y inhibited LT formation with IC50s in mouse macrophages and human whole blood of 3 nM and 0.02 microM, respectively. 4y did not inhibit the synthesis of cyclooxygenase (CO) products at concentrations up to 500 microM in human blood, a selectivity for 5-LPO over CO of greater than 20,000-fold. In the rat 4y inhibited the formation of LTB4 in blood ex vivo and in inflammatory exudate with ED50s 3 h after oral dosing of 0.9 and 0.3 mg/kg, respectively. 4y was more potent in vitro in human whole blood and in rat blood ex vivo at 3 h than either the 5-LPO inhibitor A-64077 or the FLAP antagonist MK-886. Based on these data 4y (ICI D2138) has been entered into development as an orally active, selective 5-LPO inhibitor for clinical evaluation in inflammatory conditions in which LTs are believed to play a role.

The preclinical pharmacology of "Arimidex" (anastrozole; ZD1033)--a potent, selective aromatase inhibitor.

Anastrozole is a comparatively simple, achiral benzyltriazole derivative, 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-++ +methylpropiononitrile), that inhibits human placental aromatase with an IC50 of 15 nM and elicits maximal activity in vivo in rats (inhibition of ovulation and androstenedione-induced uterine hypertrophy) and monkeys (lowering of plasma oestradiol) at 0.1 mg/kg p.o. At 30 times this dose, anastrozole does not elevate plasma 11-deoxycorticosterone in monkeys, and at 100 times this dose, does not affect plasma aldosterone levels or Na+/K+ excretion in rats, plasma K+ concentrations in dogs, or cause adrenal hypertrophy in rats or dogs. It therefore has no discernible effect on adrenocorticoid hormone synthesis in vivo at very large multiples of its maximally effective aromatase-inhibiting dose. At similar large multiples in rats it displays no oestrogenic, anti-oestrogenic, androgenic, anti-androgenic, progestogenic, glucocorticoid, antiglucocorticoid or mineralocorticoid activity. Anastrozole is thus a potent and highly selective aromatase inhibitor, with no intrinsic hormonal activities--a pharmacological profile particularly suitable for the treatment of breast cancer.

Inhibition of prolyl 4-hydroxylase in vitro and in vivo by members of a novel series of phenanthrolinones.

Examples of a novel series of phenanthrolinones are shown to be potent competitive inhibitors of avian prolyl 4-hydroxylase, and of collagen hydroxylation, in embryonic chick tendon cells and human foreskin fibroblasts in vitro and in the oestradiol-stimulated rat uterus in vivo. Two compounds, Compound 1 (1,4-dihydrophenanthrolin-4-one-3-carboxylic acid) and Compound 5 [8-(N-butyl-N-ethylcarbamoyl)-1,4-dihydrophenathrolin-4-one-3-carboxylic acid], with comparable potencies in vivo, were chosen to investigate the effect of the inhibition of the hydroxylation of newly synthesized uterine collagen on the turnover of this protein in vivo. Inhibition of hydroxylation by more than 50% for approx. 8 h following single oral doses of the compounds was associated with significant losses of radiolabelled proline and 4-hydroxyproline from collagen during this period. Progressive hydroxylation of collagen over 48 h, as the inhibitory action of the compounds declined, was accompanied by a decreased loss of radiolabel from the uterine collagen. Earlier reports indicated that underhydroxylated collagen, accumulating within the endoplasmic reticulum in cells where prolyl 4-hydroxylase is inactivated, is slowly degraded, but is then rapidly hydroxylated and secreted when the activity of prolyl 4-hydroxylase is restored. Taken with the present results, this suggests that the potential use of inhibitors of prolyl 4-hydroxylase to control excessive collagen deposition in pathological fibrosis may be limited by the need to maintain continuous inhibition of collagen hydroxylation so as to facilitate intracellular degradation of the accumulated protein.

Structure and activity relationships leading to the discovery of ICI D2138, a selective, potent and orally active inhibitor of 5-lipoxygenase.

Structure and activity relationships of (methoxyalkyl)thiazole and 4-methoxytetrahydropyran series of 5-lipoxygenase inhibitors are reviewed. One member of the 4-methoxytetrahydropyran series, 6-([fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]methyl) -1- methylquinol-2-one (ICI D2138), is undergoing clinical evaluation.