Leukotriene receptor antagonists. 1. Synthesis and structure-activity relationships of alkoxyacetophenone derivatives

Marshall, Winston S.; Goodson, Theodore; Cullinan, George J.; Swanson-Bean, Dorothy; Haisch, K. D.; Rinkema, L. E.; Fleisch, Jerome H.

doi:10.1021/jm00387a018

Cited by 59 publications

(15 citation statements)

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“…Various examples from the literature show that the pharmacodynamic effect can increase, decrease, or completely disappear. [24] Through the substitution of a carboxylic acid by a 5-ST, its in vitro activity was increased by approximately thirty times, probably due to a better interaction between the delocalized negative charge on the tetrazole ring and the arginine residue in the active site of the cysLT 1 receptor for LTD 4 . One of the first in vivo studies found that the tetrazole analogue of nicotinic acid was excreted unchanged, whereas nicotinic acid itself was quickly metabolized.…”

Section: -Sts In Medicinal Chemistrymentioning

confidence: 99%

Synthesis and Functionalization of 5‐Substituted Tetrazoles

2012

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Tetrazoles are synthetic heterocycles with numerous applications in organic chemistry, coordination chemistry, the photographic industry, explosives, and, in particular, medicinal chemistry. In organic chemistry, 5‐substituted tetrazoles are used as advantageous intermediates in the synthesis of other heterocycles and as activators in oligonucleotide synthesis. In drug design, 5‐monosubstituted tetrazoles are the most important tetrazole derivatives because they represent non‐classical bioisosteres of carboxylic acids, with similar acidities but higher lipophilicities and metabolic resistance. In this review we focus on the preparation and further functionalization of these heterocycles. Firstly, the role of 5‐substituted tetrazoles in medicinal chemistry is described, including examples of their effects on pharmacokinetics, pharmacodynamics, and metabolism of the associated drugs. Then, the main synthetic approaches to 5‐substituted tetrazoles – consisting of methods based on acidic media/proton catalysis, Lewis acids, and organometallic or organosilicon azides – are presented, from the early procedures to the most recent ones, with special attention paid to the reaction mechanisms. Functionalization of 5‐substituted tetrazoles is a challenging task because it usually leads to the formation of two isomers, 1,5‐ and 2,5‐disubstituted tetrazoles, in various ratios. In this overview, reactions with high or unusual regioselectivities are described, with comments on the possible mechanisms. Microwave‐assisted approaches to the synthesis and functionalization of 5‐substituted tetrazoles are also included.

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Section: -Sts In Medicinal Chemistrymentioning

confidence: 99%

Synthesis and Functionalization of 5‐Substituted Tetrazoles

2012

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“…We speculate through the investigation of a series of chemically modified compounds with similar structure (not shown) and from other reports (Feuer, 1977;1981;Dhai, 1979) that the serum ALT lowering effect is due to the thiadiazol structure at 3-methyl position of the YM-16638 molecule; however, we still have insufficient data to confirm this point. LY-171883 (Eli Lilly Co., Ltd., U.S.A.), a potent and leukotriene antagonist with a similar structure to YM-16638, (Marshall et al, 1987;Fleisch et al, 1985) is known to decrease serum triglyceride level in rats and monkeys, but not serum cholesterol level and ALT activity (Eacho et al, 1985;Foxworthy et al, 1990;Hoover et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Species specificity in the blood cholesterol‐lowering effect of YM‐16638

Goto¹,

Shimokawa²,

Ugawa³

et al. 1996

British J Pharmacology

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. The compound YM‐16638, [[5‐[[3‐(4‐acetyl‐3‐hydroxy‐2‐propylphenoxy)propyl]thio]‐1,3,4‐thiadiazol‐ 2‐yl]thio] acetic acid was developed in a series of in vitro and in vivo studies as a leukotriene D4 receptor antagonist. . In a clinical trial as a leukotriene antagonist drug, this compound was found to have a potent serum cholesterol lowering effect in normolipidaemic healthy male volunteers. . In the present study, we investigated the serum cholesterol lower effect of this compound in various species of experimental animals. . Administration of YM‐16638 did not cause a significant decrease in serum total cholesterol (TC) in mice (up to 200 mg kg−1, body weight per day for 28 days), rats (200 mg kg−1 for 15 days) or rabbits (90 mg kg−1 for 18 days). In hamsters, administration of YM‐16638 orally or by peritoneal injection at 50 mg kg−1 or more daily for 7 days caused a significant decrease in serum TC and the rate of body weight gain. In monkeys, serum TC did not change in YM‐16638‐administered squirrel monkeys (50 mg kg−1 daily for 3 weeks), but a significant decrease in serum TC was observed in cynomolgus monkeys (33% decrease at 30 mg kg−1 for 4 weeks) and rhesus monkeys (27% decrease at 30 mg kg−1 for 3 weeks) without any serious decrease in body weight. These results were consistent with those in a phase I study in human subjects. In contrast, serum alanine aminotransferase (ALT) level decreased in all animals after YM‐16638 treatment. . From these results, we conclude that YM‐16638 has a potent hypocholesterolaemic effect, but that this effect if species‐specific and is only recognized clearly in human subjects and old‐world monkeys.

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“…During the past 15 years several potent and selective CysLT 1 antagonists have been developed (Scheme 1). 14 At first the development of new CysLT 1 antagonist was mainly inspired by FPL 55712 22 or LTD 4 analogues, e.g. probilukast (SK&F 104353).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT₁ (LTD₄) Receptor Antagonists

Zwaagstra¹,

Timmerman²,

Tamura³

et al. 1997

J. Med. Chem.

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The synthesis and CysLT1 antagonistic activities of a new series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-position. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1-methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lower activities [1-(1-ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'-, or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen-induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1 microM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.

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Leukotriene receptor antagonists. 1. Synthesis and structure-activity relationships of alkoxyacetophenone derivatives

Cited by 59 publications

References 0 publications

Synthesis and Functionalization of 5‐Substituted Tetrazoles

Synthesis and Functionalization of 5‐Substituted Tetrazoles

Species specificity in the blood cholesterol‐lowering effect of YM‐16638

Synthesis and Structure−Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT₁ (LTD₄) Receptor Antagonists

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Leukotriene receptor antagonists. 1. Synthesis and structure-activity relationships of alkoxyacetophenone derivatives

Cited by 59 publications

References 0 publications

Synthesis and Functionalization of 5‐Substituted Tetrazoles

Synthesis and Functionalization of 5‐Substituted Tetrazoles

Species specificity in the blood cholesterol‐lowering effect of YM‐16638

Synthesis and Structure−Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT1 (LTD4) Receptor Antagonists

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Synthesis and Structure−Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT₁ (LTD₄) Receptor Antagonists