The stereospecific formation of 2-aryl-β-methyl tryptamine derivatives 15 and 16 from chiral 4-chloro-1-(3,5-dimethylphenyl)-3-methylbutanones is described. These intermediates were further manipulated into the GnRH antagonists 1b and 1c in five steps.

Carboxyalkyl peptides containing a biphenylylethyl group at the P-1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P-1', a tert-butyl group at P-2', and a methyl group at P-3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P-1'-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P-1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl -1,5-pentanedioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a K-i of 10 nM against MMP-3 and an ED(50) of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED(50) = 6 mg/kg iv).

Systematic modification of the C6 acyl side chain of zaragozic acid A, a potent squalene synthase inhibitor, was undertaken to improve its biological activity. Simplification of the C6 side chain to the octanoyl ester has deleterious effects; increasing the linear chain length improves the in vitro activity up to the tetradecanoyl ester. An omega-phenoxy group is a better activity enhancer than an omega-phenyl group. A number of C6 carbamates, ethers, and carbonates were prepared and found to have similar activity profiles as the C6 esters. In the preparation of C6 ethers, C4 and C4,6 bisethers were also isolated; their relative activity is: C6 > C4 > C4,6. These C6 long-chain derivatives are subnanomolar squalene synthase inhibitors; they are, however, only weakly active in inhibiting hepatic cholesterol synthesis in mice. The C6 short-chain derivatives are much less active in vitro, but they all have improved oral activity in mice. Modification of the C1 alkyl side chain of the n-butanoyl analogue (ED50 4.5 mg/kg) did not improve the po activity further. A number of these C6 long-chain derivatives are also potent antifungal agents in vitro.

An efficient chemical sequence is described for the modification of the C-4′ and C-6 positions of zaragozic acid A. Key reactions include the specific conditions devised for selective removal of either the C-4′ acetate or the C-6 acyl chain. The resultant hydroxy intermediates were then derivatized as esters, ethers, carbamates, and carbonates.

(-)-trans-(2S,5S)-2-[3-[(2-Oxopropyl)sulfonyl]-4-n-propoxy-5-(3- hydroxypropoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (10) is one of the most potent platelet-activating factor (PAF) antagonists in vitro and in vivo developed to date. This diaryltetrahydrofuran derivative evolved from modifications of MK 0287 which has been evaluated in clinical studies for asthma. Two structural modifications of MK 0287 were made: (1) elaboration of the 3'-[(hydroxyethyl)sulfonyl] group to a beta-keto propylsulfonyl, and (2) replacement of the 5'-methyl ether by a 3-hydroxypropyl ether. Compound 10 potently and specifically inhibits the binding of [3H]-C18-PAF to human platelet membranes (Ki 1.85 nM) and PMN membranes (Ki 2.89 nM). In vivo, 10 inhibits PAF-induced plasma extravasation and elevated N-acetyl-beta-D-glucosaminidase (NAGA) levels in male rats with ED50 values of 60 micrograms/kg, po and 4 micrograms/kg, iv respectively, and inhibits PAF-induced bronchoconstriction in guinea pigs with an ED50 value of 15 micrograms/kg after intraduodenal administration. Compound 15, a water-soluble phosphate ester prodrug derivative of 10 is at least equipotent to 10 in the in vivo models. Compound 19S, the primary and major metabolite of 10 and 15, is equipotent in in vitro and in vivo models.

(±)-trans-2-(3-Methoxy-4-phenylsulfonylethoxy-5-n-propylsulfonylphenyl)tetrahydrofuran (L-671,284) is a highly potent, selective, competitive PAF-receptor antagonist with a Ki of 1.0 nM for inhibition of binding of [3H]C18-PAF to human platelets and exhibits little or no gender differences in bioactivities in rats. Several 4′ positional analogs of L-671,284 have been synthesized and evaluated in vitro.

An enantioselective synthesis of MK 287 (L-680,573), a member of a family of trans-2,5-diaryltetrahydrofurans, and its biological activity are described.

1. The plasma concentration, main route of metabolism and excretion of 3H-L-659,989 were studied in male and female rhesus monkeys by dosing either i.v. or orally at 10 mg/kg. 2. The percentage of the AUC for the plasma radioactivity concentration-time curve of oral vs i.v. dosed monkeys was 78% for males and 90% for females, indicating that the dose was well absorbed. 3. The bioavailability of the drug was low (less than or equal to 10%) for all monkeys, probably due to rapid first pass metabolism. The drug was metabolized-predominantly at the C-4'-propoxy side-chain. The two major plasma metabolites were identified as the 4'-2-(hydroxy)propoxy metabolite (3H-trans-4'-HP) and the 4'-hydroxy metabolite (3H-4'-hydroxy) which was isolated as a 2:1 mixture of (+/-)trans: (+/-)cis. 4. Approx. 80% of the radiolabelled dose was excreted equally in the urine and faeces in 96 h, with the largest percentage of the tritiated dose (31 +/- 4%) in the 0-24 h urine. 5. The major metabolites in the excreta were the (+/-)trans/(+/-)cis mixture of 3H-4'-hydroxy and the glucuronide conjugate of 3H-trans-4'-hydroxy. The glucuronide conjugate of 3H-trans-4'-hydroxy was excreted in the urine of i.v. and orally dosed monkeys and represented an average of 21% and 5.1% of the dose, respectively. 3H-4'-Hydroxy was excreted in both the urine and faeces, accounting for less than or equal to 0.1% and 7.4% of the dose in i.v. and orally dosed monkeys, respectively.

L-659,989 [trans-2-(3-methoxy-5-methylsulfonyl-4-propoxy-phenyl)-5-(3,4,5- trimethoxyphenyl)tetrahydrofuran] is a p.o. active and extremely potent, selective and competitive platelet-activating factor (PAF) receptor antagonist. It inhibited [3H]PAF binding to either rabbit platelet or rabbit polymorphonuclear leukocyte membranes with an equilibrium inhibition constant (Kl) of 1.1 nM; whereas in human platelet, human polymorphonuclear leukocyte or human lung membranes, L-659,989 was about 10 times less potent with a Kl of 14.3 nM. The structural specificity of L-659,989 was demonstrated by the low activity of its cisisomer which was about 100 to 200 times less potent, also the (-)-L-659,989 was found to be 20- to 30-fold more potent than (+)-L-659,989. In both [3H]PAF binding and PAF-induced platelet aggregation inhibition, L-659,989 was found to be a competitive inhibitor with an equilibrium dissociation constant (KB) of 1.5 and 1.7 nM, respectively, in rabbit platelets. Even up to 6 microM concentration, L-659,989 showed no inhibition on the aggregation of rabbit platelets in plasma induced by ADP, arachidonic acid, collagen or thrombin. In an in vivo model, it inhibited guinea pig bronchoconstriction induced by i.v. infusion of 75 ng/kg of PAF with ED50 values of 13 micrograms/kg i.v. and 0.5 mg/kg p.o.

The title compound, L-659,989, is a highly potent, competitive, and selective antagonist of the binding of [3H]PAF to its receptors in platelet membranes from rabbits and humans. It exhibits equilibrium inhibition constants for PAF binding of 1.1 nM (rabbit) to 9.0 nM (human), values that are at least 1-2 orders of magnitude lower than those of other PAF antagonists tested. L-659,989 potently inhibits PAF-induced aggregation of rabbit platelets and degranulation of rat (ED50 4.5 nM) and human (ED50 10 nM) neutrophils. L-659,989 inhibits PAF-induced extravasation and lysosomal enzyme release in rats, and is active orally in female rats (ED50 0.2 mg/kg) with an extraordinary oral duration of action of 12 to 16 hours at 1.0 mg/kg p.o.

Acid catalyzed cyclization of (1R,4RS)- and (1S,4RS)-1-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)butane-1,4-diols to the corresponding chiral cis- and trans-tetrahydrofurans proceeds with retention of configuration at C-1. Using this stereo- and regioselective reaction, the two optically active enantiomers of L-659,989, a potent PAF-receptor antagonist, were prepared.

Abstract(PONPIPOM , M.M.; BUGIANESI, R.L.; BROOKER, D.R.; YUE, B.‐Z.; HWANG, S.‐B.; SHEN, T.‐Y.; J. Med.

ChemInformVolume 18, Issue 37 Natural Products ChemInform Abstract: Inhibition of Delayed Hypersensitivity Reactions by Cinnamyl 1-Thioglycosides. M. M. PONPIPOM, M. M. PONPIPOM Merck Sharp&Dohme Res. Lab., Rahway, NJ 07065, USASearch for more papers by this authorR. L. BUGIANESI, R. L. BUGIANESI Merck Sharp&Dohme Res. Lab., Rahway, NJ 07065, USASearch for more papers by this authorT. J. BLAKE, T. J. BLAKE Merck Sharp&Dohme Res. Lab., Rahway, NJ 07065, USASearch for more papers by this author M. M. PONPIPOM, M. M. PONPIPOM Merck Sharp&Dohme Res. Lab., Rahway, NJ 07065, USASearch for more papers by this authorR. L. BUGIANESI, R. L. BUGIANESI Merck Sharp&Dohme Res. Lab., Rahway, NJ 07065, USASearch for more papers by this authorT. J. BLAKE, T. J. BLAKE Merck Sharp&Dohme Res. Lab., Rahway, NJ 07065, USASearch for more papers by this author First published: September 15, 1987 https://doi.org/10.1002/chin.198737314Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References M. M. PONPIPOM, R. L. BUGIANESI, T. J. BLAKE, Inhibition of Delayed Hypersensitivity Reactions by Cinnamyl 1-Thioglycosides., J. Med. Chem., 1987, 30, 705. DOI: 10.1021/jm00387a021; 10.1021/jm00387a021 CASPubMedWeb of Science®Google Scholar Volume18, Issue37September 15, 1987 ReferencesRelatedInformation