Second Generation Leukotriene B4 Receptor Antagonists Related to SC-41930: Heterocyclic Replacement of the Methyl Ketone Pharmacophore

Abstract

Our previous reports have highlighted the first-generation leukotriene B4 (LTB4) receptor antagonist SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) which has potent oral, topical, and intracolonic activity in various animal models of inflammation. Extensive structure-activity relationship studies, in which a series of heterocyclic replacements for the methyl ketone functional group of SC-41930 was explored, identified SC-50605 (7-[3-[2-(cyclopropylmethyl)-3-methoxy-4- (4-thiazolyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- carboxylic acid) as an optimized analog within a series of thiazoles. SC-50605 was found to be significantly more potent than SC-41930 in LTB4 receptor binding, chemotaxis, and degranulation assays. It also displayed very good activity in animal models of colitis and epidermal inflammation by oral, topical, intravenous, and intracolonic routes of administration. The resolved enantiomers of SC-50605 were obtained by chiral chromatography and both demonstrated good in vitro and in vivo activity. The (+)-isomer (SC-52798) is currently being evaluated as a potential clinical candidate for psoriasis and ulcerative colitis therapy.

Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

“…Single nucleotide polymorphisms spanning the LTA4H gene have also been correlated with increased risk of asthma and allergy susceptibility . The importance of LTA4H as a therapeutic target is exemplified by the development of multiple inhibitors representing different chemotypes. − …”

“…31 The importance of LTA4H as a therapeutic target is exemplified by the development of multiple inhibitors representing different chemotypes. [32][33][34][35][36][37][38][39][40][41][42][43] The active site pocket of LTA4H is a 17 A ˚long L-shaped cleft capable of binding the leukotriene A4 substrate. The crystal structure of LTA4H 26 was originally solved bound to bestatin (1), a low molecular weight secondary metabolite of Streptomyces olivoreticuli 44 and a component of the FOL library.…”

Synthesis and Evaluation of a New Generation of Orally Efficacious Benzimidazole-Based Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors as Anticancer Agents

“…In situ formation of thioformamide with P 2 S 5 and formamide followed by the addition of MgCO 3 converted 14 to thiazole 15. 29 The 2-methyloxazole derivative 16 was prepared when 14 was heated in urea and acetic acid. Reacting 14 with thiourea in ethanol and water at 80 °C afforded 2-aminothiazole 17.…”

“…This ring closure strategy was shown in the early work by Griffin et al and later modified by White et al and Barkalow et al Subsequent bromination using NBS and catalytic BPO in TFA gave the versatile α-bromo ketone intermediate 14 , setting the stage for a number of different transformations. In situ formation of thioformamide with P 2 S 5 and formamide followed by the addition of MgCO 3 converted 14 to thiazole 15 . The 2-methyloxazole derivative 16 was prepared when 14 was heated in urea and acetic acid.…”

The role of leukotrienes in the pathophysiology of inflammatory disorders: Is there a case for revisiting leukotrienes as therapeutic targets?

“…No clinical data are available on this compound so far. Also, second-generation of LTB 4 receptor antagonists (S41930, SC-53228 and A-69412) have been developed with the view that they could be beneficial in treating psoriasis and UL (Penning et al, 1995;Fretland et al, 1995;Bell et al, 1993).…”