Optimization of Imidazole 5-Lipoxygenase Inhibitors and Selection and Synthesis of a Development Candidate

Abstract

The leukotrienes (LTs) are endogenous mediators with potent biological activity. It is known that leukotriene B 4 (LTB 4 ) is a potent chemotactic agent for leukocytes while peptide leukotrienes (i.e., LTC 4 , LTD 4 and LTE 4 ) are powerful bronchoconstrictor agents. 5-Lipoxygenase (5-LO) is the key enzyme in LT biosynthesis and catalyzes the initial steps in conversion of arachidonic acid to LTs.1,2) Accordingly, inhibiting the action of 5-LO and antagonizing the action of LTs are expected to be valuable for the treatment of acute and chronic diseases such as asthma, allergic rhinitis and psoriasis. It has been shown that 5-LO inhibitors and LTD 4 antagonists are efficacious in asthmatics. 3-7)We have disclosed on imidazole compound 1 as a novel orally active 5-LO inhibitor (Chart 1). Shortcomings of 1 were unsatisfactory pharmacokinetic profile and unwanted side effects (ocular). Preliminary structure-activity relationships (SARs) identified novel imidazole lead-compound 2 with modest oral pharmacology and improved pharmacokinetic profile. 8,9) Importantly, compared with 1, ocular toxicity of 2 was significantly reduced. In this paper, we disclose our efforts focused on optimization of 2 leading to the discovery of clinical candidate, a novel 5-LO inhibitor void of ocular toxicity as assessed in preclinical models. ChemistryImidazole compounds 3-8 were synthesized for this study. Compounds 3 and 8 were synthesized as shown in Chart 2. Phenol 10, which was obtained by demethylation of known 3,4,5,6-tetrahydro-2H-pyran (THP) compound 9, 10) was treated with benzyl chloride 11 in the presence of K 2 CO 3 to give ether 12.8) Selective hydrolysis of nitrile 12 gave amide 3 (approximately 4 equivalents of powdered KOH in tBuOH at 80°C).11) Similarly, nitrile 15, which was obtained by coupling of 10 with iodide 14 in the presence of cupric oxide, was converted to amide 8.Chart 3 illustrates the synthesis of 4. Aldehyde group was selectively introduced to commercially available 2,5-difluorophenol 16 to give 19, which was converted to methyl aphenyl acetate derivative 22 in a stepwise manner. THP ring was constructed by the method reported for the preparation of 2.9) The THP 23 was demethylated to phenol 24, which was treated with benzyl chloride 11 to give imidazole ester 25. The ester 25 was converted to amide 4 by standard procedure. 9)Synthesis of 5 is depicted in Chart 4. Difluorobenzene 26 11) was converted to the monomethylthioether 27. Oxidation of 27 to the corresponding sulfoxide 28 followed by Pummerer rearrangement yielded thiophenol 29. Palladiumcatalyzed coupling of 29 with iodide 14 gave nitrile 30, which was selectively hydrolyzed to yield amide 5.Chart 5 shows the syntheses of 6 and 7. Ester 32, synthesized from ethyl (3-bromophenyl)acetate, was converted to intermediate methyl thioether by lithium-bromine exchange of carboxylic acid 33 with n-buthyl lithium followed by treatment with dimethyl disulfide. The intermediate methyl thioether was converted to 35 via sulfoxide 34. Palladiumcatalyzed coupling...

Itraconazole-mediated inhibition of calcium entry into platelet-activating factor-stimulated human neutrophils is due to interference with production of leukotriene B4

“…This contention is based on a previous report that the production of prostaglandin E2 by human neutrophils activated with the calcium ionophore, A23187 is unaffected by itraconazole [10], and our own unpublished observations that the generation of arachidonic acid by A23187 (1 mM)-activated human neutrophils is insensitive to the anti-mycotic. Although involvement of FLAP cannot be excluded, the direct inhibitory effects of itraconazole on purified 5-LO suggest that this is the primary target of the anti-mycotic, which is in keeping with the well-recognized inhibitory interactions of pharmacological agents which possess an imidazole moiety with this enzyme [18,19]. It is noteworthy, however, that the inhibitory effects of itraconazole on purified 5-LO were of lesser magnitude than those observed with LTB4 production by PAF-activated neutrophils.…”

Lens cholesterol biosynthesis inhibition: A common mechanism of cataract formation in laboratory animals by pharmaceutical products

“…The rank order of cataractogenic potential in vivo was determined to be: CJ‐12,918 > CJ‐13,454 > > > ZD‐2138. After blocking all three metabolic sites on CJ‐12,918, CJ‐13,610 emerged as the clinical candidate after showing higher parent systemic exposure and drug levels in the rat lens with no evidence of cataract formation in a 1‐month rat exploratory study at 250 mg/kg/day (Table ) and longer‐term studies of 3 months duration in rats (150 mg/kg/day) and dogs (30 mg/kg/day, where C max values of ~13 and ~8 μg/mL were achieved, respectively (Mano et al, ).…”

Pharmacology of PF-4191834, a Novel, Selective Non-Redox 5-Lipoxygenase Inhibitor Effective in Inflammation and Pain

“…PF-4191834 is a potent competitive inhibitor of the 5-LOX enzyme that arose from chemical modifications to the prototype CJ-13,610 (Fischer et al, 2004;Mano et al, 2005), resulting in a more potent agent with clear pharmacodynamic improvements. PF-4191834 is a noniron chelating, non-redox inhibitor of the 5-LOX enzyme that is being developed as an oral anti-inflammatory therapy for the treatment of asthma.…”