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PubMed1998

Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential.

N-Ethyl-5-trifluoromethyl-2-aminoindan (ETAI) and 5-trifluoromethyl-2-aminoindan (TAI) were synthesized to examine the effects of side-chain cyclization on the pharmacology of the anorectic drugs fenfluramine (FEN) and norfenfluramine (norFEN), respectively. ETAI and TAI inhibited synaptosomal accumulation of 5-HT but were less effective at inhibiting catecholamine uptake than FEN or norFEN, respectively. In vivo, ETAI and TAI were less neurotoxic than FEN or norFEN; decreases in the number of [3H]paroxetine-labeled 5-HT uptake sites were 50% less than the decreases produced by FEN or norFEN. Rats treated with ETAI. TAI, FEN, and norFEN lost 10-15% of their pretreatment body weight over a 4-day period, while saline-treated control animals gained 8%. In two-lever drug discrimination (DD) assays in rats, TAI fully substituted for the 5-HT releaser/uptake inhibitor, (+)-MBDB [(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane]. ETAI produced only partial substitution in this test. Neither TAI nor ETAI mimicked (+)-amphetamine in the DD assay. These studies demonstrate that incorporation of the side-chain of phenylisopropylamines into the five-membered ring of a 2-aminoindan changes both the molecular pharmacology and the neurotoxic profile of FEN and norFEN, but does not diminish the drugs' ability to reduce body weight.

Animals↗
PubMed2002

N-[2-(Indan-1-yl)-3-mercapto-propionyl] amino acids as highly potent inhibitors of the three vasopeptidases (NEP, ACE, ECE): In vitro and In vivo activities.

We have previously reported the design of a lead compound 1a for the joint inhibition of neprilysin (NEP, EC 3.4.24.11), angiotensin converting enzyme (ACE, EC 3.4.15.1) and endothelin converting enzyme (ECE-1, EC 3.4.24.71), three metallopeptidases which are implicated in the regulation of fluid homeostasis and vascular tone. We report here the synthesis and biological activities of analogues derived from this lead with inhibitory potencies in the nanomolar range for the three enzymes. Compounds 8b and 15c are the most potent triple inhibitors described to date.

Amino Acids↗
PubMed1994

New potent prolyl endopeptidase inhibitors: synthesis and structure-activity relationships of indan and tetralin derivatives and their analogues.

New compounds were synthesized by structural modification of 1-[1-(4-phenylbutanoyl)-L-prolyl]-pyrrolidine (SUAM-1221, 1) or 1-[1-(benzyloxycarbonyl)-L-proly]prolinal (Z-Pro-prolinal,2) and were tested for in vitro inhibitory activities against purified prolyl endopeptidase (PEP) from canine brain. In a series of compounds which lack a formyl or a cyano group, 3-[3-[(S)-2-(1,2,3,4-tetrahydronaphthyl)acetyl]-L- thioprolyl]thiazolidine (13) exhibited an approximately 20-fold (IC50 = 2.3 nm) increase in potency compared with 1. Compounds having a formyl or a cyano group showed much more potent inhibitory activities than those which lack such a functional group. Among all compounds tested in vitro, 1-[1-(2-indanylacetyl)-L-prolyl]prolinal (27), 1-[1-[(S)-2-(1,2,3,4-tetrahydronaphthyl)acetyl]-L- prolyl]prolinal (29), 1-[3-[(S)-2-(1,2,3,4-tetrahydronaphthyl)-acetyl]-L-thioprolyl]p rolinal (30), (S)-2-cyano-1-[2-[(S)-2-(1,2,3,4-tetrahydronaphthyl)acetyl]-L- prolyl]pyrrolidine (34), and (S)-2-cyano-1-[3-[(S)-2-(1,2,3,4-tetrahydronaphthyl)acetyl]-L- thioprolyl]pyrrolidine (35) showed an approximately 2-fold (IC50 congruent to 0.5 nM) increase in potency compared with 2. The structure-activity relationships of these compounds are discussed.

Animals↗
PubMed1989

Thromboxane A2 synthetase inhibitors. 2. Syntheses and activities of tetrahydronaphthalene and indan derivatives.

A series of 1-imidazolylalkyl-substituted or 5-thiazolylalkyl-substituted tetrahydronaphthalenecarboxylic acid and indancarboxylic acid derivatives were prepared and tested for the inhibitory activities of thromboxane A2 (TXA2) production in vitro and ex vivo. Most of the compounds showed potent TXA2 synthetase inhibitory activities in vitro and had long duration of inhibition of TXA2 production in rats when orally or intravenously administrated. The imidazole analogues had slightly less potency in vitro than the thiazole analogues, but the activities of the imidazole analogues in ex vivo models were equal or superior to the activities of the thiazole analogues. 6-(1-Imidazolyl-methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride hemihydrate (47a, DP-1904) was chosen for clinical studies.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA).

Four cyclic analogues of the psychoactive phenethylamine derivative 3,4-(methylenedioxy)amphetamine were studied. These congeners, 5,6- and 4,5-(methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and 5,6-(methylenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Two groups of rats were trained to discriminate either LSD tartrate (0.08 mg/kg) from saline, or (+/-)-MDMA.HCl (1.75 mg/kg) from saline. In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine 1-(2,5-dimethoxy-4- methylphenyl)-2-aminopropane (DOM) were also evaluated. None of the methylenedioxy compounds substituted in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained rats. Compounds 4a and 4b did not substitute in MDMA-trained rats. Compounds 5a and 5b did not substitute in MDMA-trained rats, although 5a substituted in LSD-trained rats, but with relatively low potency compared to its open-chain counterpart. In view of the now well-established serotonin neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue 1, 3a and 3b were evaluated and compared to 1 for similar toxic effects following a single acute dose of 40 mg/kg sc. Sacrifice at 1 week showed that neither 3a nor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA levels nor were the number of binding sites (Bmax) depressed for [3H]paroxetine. By contrast, and in agreement with other reports, 1 significantly depressed all three indices of neurotoxicity. These results indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but that they lack similar serotonin neurotoxicity.

3,4-Methylenedioxyamphetamine↗
PubMed1978

Antiinflammatory and analgesic diastereoisomeric derivatives of indan-5-acetic acid.

Various 2-alkyl-alpha-methyl- and 2-alkylindan-5-acetic acids have been prepared. The acids, which can exist in two diastereoisomeric forms that cannot be separated by crystallization or chromatography, can be analyzed in their mixture by NMR in the presence of Eu(dpm)3. It has been possible to reconstitute the two pure racemic 2-isopropyl-alpha-methylindan-5-acetic acids from their enantiomers obtained after resolution of the mixtures through salts with various active bases. The relative configuration of the two asymmetric centers of one of the diastereoisomers salts with various active bases. The relative configuration of the two asymmetric centers of one of the diastereoisomers has been determined by X-ray crystallography. The absolute configurations of the resolved acids have been established by a comparative study of their CD curves. The antiinflammatory and analgesic properties of these compounds as functions of their structure and stereochemistry are discussed.

Animals↗
PubMed1984

Resorcinol congeners of dopamine derived from benzocycloheptene and indan.

Series of N-alkylated derivatives of 2-amino-4,6-dihydroxyindan 3 and 6-amino-1,3-dihydroxybenzocycloheptene 2 were prepared for pharmacological testing as congeners of 2-amino-5,7-dihydroxytetralin, which elicits dopaminergic effects in a variety of assays. All of the subject compounds demonstrated a lower order of dopamine-like activity than the tetralin derivatives. Some of the subject compounds showed weak interactions with alpha 1- and beta 1-adrenoceptors, but the major determinant of activity seemed to be the nature of the N-alkyl substituent rather than ring size.

Animals↗
PubMed2002

Comparative study of anionic and radical cyclization for the preparation of 1,3-dimethylindans: highly stereoselective preparation of cis-1,3-disubstituted indans via intramolecular carbolithiation.

[reaction: see text] The preparation of 1,3-dimethylindans from 4-(2-bromophenyl)-1-pentene (1) and 2-(2-iodo-1-methylethyl)styrene (2) substrates via radical-mediated cyclization and intramolecular carbolithiation has been investigated. Although cyclization of the radical derived from either substrate proceeds with modest selectivity for the cis-isomer, as does cycloisomerization of the aryllithium derived from substrate 1 (cis/trans approximately 2), intramolecular cyclization of the alkyllithium derived from substrate 2 is a highly cis-selective process (cis/trans = 12).

Anions↗
PubMed2004

ATP-dependent transport of a novel thromboxane A2 receptor antagonist, [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335) and its xenobiotic taurine conjugate (Z-335-Tau) by rat bile canalicular membrane vesicles.

PURPOSE: The characteristics of bile canalicular transport processes for xenobiotic taurine conjugates have not yet been clarified. To elucidate the biliary excretion characteristics of xenobiotic taurine conjugates, we investigated the transport of a novel thromboxane A2 receptor antagonist, Z-335, and its taurine conjugate (Z-335-Tau) across the bile canalicular membrane. METHODS: We examined the uptake of Z-335 and Z-335-Tau by isolated bile canalicular membrane vesicles (CMVs) from Sprague Dawley and Eisai-hyperbilirubinemic rats (EHBRs) which EHBRs have a hereditary defect of canalicular multidrug resistance-associated protein 2 (Mrp2) function. Also, the in vitro and in vivo kinetics of Z-335-Tau uptake and excretion were compared. RESULTS: Z-335 uptake by CMVs from normal rats exhibited marked ATP-dependence, whereas ATP-dependent uptake of Z-335 into CMVs from EHBRs was not observed. In contrast, Z-335-Tau uptake into CMVs from both normal rats and EHBRs was ATP dependent. The initial uptake velocity was concentration-dependent, with an in vitro Michaelis constant for initial uptake of 189 microM, which was similar to the in vivo value. CONCLUSIONS: The biliary excretion of Z-335 involves Mrp2, whereas that of Z-335-Tau involves active transport systems that remain intact in EHBRs and show marked ATP dependence, which ATP-dependent transport is involved in the biliary excretion of Z-335-Tau in vivo.

Acetates↗
PubMed1990

Structure of a photodimer of 3-acetoxy-2-inden-1-one: 9,10-dioxoindano[2',3':4,3]cyclobuta[1,2-b]indan-4b,4c-diyl diacetate.

C22H16O6, Mr = 376.37, monoclinic, P21/c, a = 9.555 (3), b = 15.664 (2), c = 12.300 (4) A, beta = 100.08 (2) degrees, V = 1812.5 (5) A3, Z = 4, Dx = 1.379 g cm-3, lambda(Cu K alpha) = 1.5418 A, mu = 8.0 cm-1, F(000) = 784, room temperature, R = 0.047, wR = 0.064 for 3203 observed reflections [I greater than 3 sigma (I)]. The molecule exists as the syn-trans isomer in the crystal. The crystal structure exhibits a number of C--H...O intermolecular contacts.

Chemical Phenomena↗
PubMed1985

Effect of DL-6-(N-alpha-pipecolinomethyl)-5-hydroxy-indane maleate (PMHI) on the reproductive system of a wild rat, Bandicota bengalensis.

The anti-testicular action of PMHI was investigated in a wild rodent, the bandicoot rat. Bandicoots were given a single subcutaneous injection of this compound at a dose of 150 mg/kg and were killed 2, 10, or 30 days later. PMHI induced marked and rapid testicular regression with complete arrest of spermatogenesis by day 10 such that the seminiferous tubules contained only a ring of Sertoli cells with few spermatogonia. This was also reflected by a severe depletion of the number of sperm in the cauda epididymis. However, by day 30 after PMHI injection, testicular histology indicated restoration of spermatogenesis in parallel with the time schedule of germ cell development. The results indicate that PHMI produces a reversible anti-spermatogenic effect in the bandicoot rat which appears to be time dependent.

Animals↗