BIOMAT Database Logo BIOMAT Database Logo

Methoxytetrahydropyrans. A new series of selective and orally potent 5-lipoxygenase inhibitors. 1992

G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Chemistry Department, ICI Pharmaceuticals, Macclesfield, Cheshire, UK.

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.

UI MeSH Term Description Entries
D007975 Leukotriene B4 The major metabolite in neutrophil polymorphonuclear leukocytes. It stimulates polymorphonuclear cell function (degranulation, formation of oxygen-centered free radicals, arachidonic acid release, and metabolism). (From Dictionary of Prostaglandins and Related Compounds, 1990) 5,12-HETE,5,12-diHETE,LTB4,Leukotriene B,Leukotriene B-4,Leukotrienes B,5,12 HETE,5,12 diHETE,B-4, Leukotriene,Leukotriene B 4
D008264 Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood MONOCYTES. Main types are PERITONEAL MACROPHAGES; ALVEOLAR MACROPHAGES; HISTIOCYTES; KUPFFER CELLS of the liver; and OSTEOCLASTS. They may further differentiate within chronic inflammatory lesions to EPITHELIOID CELLS or may fuse to form FOREIGN BODY GIANT CELLS or LANGHANS GIANT CELLS. (from The Dictionary of Cell Biology, Lackie and Dow, 3rd ed.) Bone Marrow-Derived Macrophages,Monocyte-Derived Macrophages,Macrophage,Macrophages, Monocyte-Derived,Bone Marrow Derived Macrophages,Bone Marrow-Derived Macrophage,Macrophage, Bone Marrow-Derived,Macrophage, Monocyte-Derived,Macrophages, Bone Marrow-Derived,Macrophages, Monocyte Derived,Monocyte Derived Macrophages,Monocyte-Derived Macrophage
D009281 Naphthalenes Two-ring crystalline hydrocarbons isolated from coal tar. They are used as intermediates in chemical synthesis, as insect repellents, fungicides, lubricants, preservatives, and, formerly, as topical antiseptics.
D010529 Peritoneal Cavity The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the STOMACH. The two sacs are connected by the foramen of Winslow, or epiploic foramen. Greater Sac,Lesser Sac,Omental Bursa,Bursa, Omental,Cavity, Peritoneal,Sac, Greater,Sac, Lesser
D011714 Pyrans Pyran
D004347 Drug Interactions The action of a drug that may affect the activity, metabolism, or toxicity of another drug. Drug Interaction,Interaction, Drug,Interactions, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000001 Calcimycin An ionophorous, polyether antibiotic from Streptomyces chartreusensis. It binds and transports CALCIUM and other divalent cations across membranes and uncouples oxidative phosphorylation while inhibiting ATPase of rat liver mitochondria. The substance is used mostly as a biochemical tool to study the role of divalent cations in various biological systems. 4-Benzoxazolecarboxylic acid, 5-(methylamino)-2-((3,9,11-trimethyl-8-(1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl)-1,7-dioxaspiro(5.5)undec-2-yl)methyl)-, (6S-(6alpha(2S*,3S*),8beta(R*),9beta,11alpha))-,A-23187,A23187,Antibiotic A23187,A 23187,A23187, Antibiotic
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
(Methoxyalkyl)thiazoles: a new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity.
July 1991, Journal of medicinal chemistry,
G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Acetohydroxamic acids as potent, selective, orally active 5-lipoxygenase inhibitors.
March 1988, Journal of medicinal chemistry,
G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Novel imidazole compounds as a new series of potent, orally active inhibitors of 5-lipoxygenase.
September 2003, Bioorganic & medicinal chemistry,
G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Methoxyalkyl thiazoles: a novel series of potent, orally active and enantioselective inhibitors of 5-lipoxygenase.
September 1991, Agents and actions,
G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Substituted chromenes as potent, orally active 5-lipoxygenase inhibitors.
November 1993, Journal of medicinal chemistry,
G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Optimization of a series of potent, selective and orally bioavailable SYK inhibitors.
October 2020, Bioorganic & medicinal chemistry letters,
G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Optimisation of a series of potent, selective and orally bioavailable GlyT1 inhibitors.
April 2009, Bioorganic & medicinal chemistry letters,
G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Potent and selective 5-lipoxygenase inhibitors: cirsiliol and AA-861.
January 1985, Advances in prostaglandin, thromboxane, and leukotriene research,
G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Azole phenoxy hydroxyureas as selective and orally active inhibitors of 5-lipoxygenase.
January 1996, Journal of medicinal chemistry,
G C Crawley, and R I Dowell, and P N Edwards, and S J Foster, and R M McMillan, and E R Walker, and D Waterson, and T G Bird, and P Bruneau, and J M Giroaeau
Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors.
August 1999, Bioorganic & medicinal chemistry letters,
Copied contents to your clipboard!