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PubMed1996

Asymmetric Synthesis. 39.(1) Synthesis of 2-(1-Aminoalkyl)piperidines via 2-Cyano-6-phenyl Oxazolopiperidine.

The asymmetric synthesis of a series of 2-(1-aminoalkyl) piperidines using (-)-2-cyano-6-phenyloxazolopiperidine 1 is described. LiAlH(4) reduction of 1 followed by hydrogenolysis led to the diamine 3. The same strategy applied to C-2-methylated compound 7 afforded [(2S)-2-methylpiperidin-2-yl]methanamine (9). Addition of lithium derivatives to the cyano group of 1 resulted in the formation of an intermediate imino bicyclic system (11a-c) which could be diastereoselectively reduced to substituted diamino alcohols 13a-c. The addition of an excess of PhLi to 1 in the presence of LiBr furnished disubstituted amine 19, the precursor of diphenyl[(2S)-piperidin-2-yl]methanamine (22).

Journal Article↗
PubMed2002

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and Prins cyclizations: a switch in diastereoselectivity between Lewis and Brønsted acid catalysts.

[reaction: see text] A novel diastereoselective approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 6a-e catalyzed by the Lewis acid methyl aluminum dichloride in refluxing chloroform affords trans piperidines 8a-e with diastereomeric ratios of up to 93:7. By contrast, Prins cyclization of 6a-e catalyzed by hydrochloric acid at low temperatures affords cis products 7a-e with diastereomeric ratios of up to 98:2.

Journal Article↗
PubMed1994

Density of NMDA-coupled and uncoupled 1-[1-(2-[3H]thienyl) cyclohexyl]piperidine recognition sites in the brain and spinal cord: differential effects of NMDA agonists and antagonists.

Binding of 1-[1-(2-[3H]thienyl)cyclohexyl]piperidine ([3H]TCP) to mouse brain and spinal cord membranes was studied using compounds selective for the NMDA-coupled 1-(1-phenylcyclohexyl)piperidine (PCP) and/or sigma recognition sites. In both tissues, [3H]TCP labeled two populations of binding sites. Density of the low-affinity sites was approximately the same in both tissues, but the population of the high-affinity [3H]TCP sites was three times bigger in the brain than in the spinal cord. Self- and cross-displacement studies showed that the high-affinity [3H]TCP binding sites could be identical with NMDA receptor-coupled PCP sites, whereas the low-affinity [3H]TCP sites may be associated with sigma binding sites in both tissues. The NMDA-coupled PCP sites labeled in the presence of 6.25 nM [3H]TCP constituted a much higher percentage of the total binding in the brain (75%) than in the spinal cord (44%). Consistent with this, reintroduction of glycine and glutamate significantly increased, but DA antagonists significantly inhibited [3H]TCP binding in the brain but not in the spinal cord. Together, these data suggest that a large component of [3H]TCP-labeled binding sites in the spinal cord may be associated with sigma but not the NMDA receptor-coupled PCP sites.

Animals↗
PubMed1980

Carcinogenicity of the isomeric, N-nitroso-delta3-and N-nitroso-delta2-piperidines in rats and the in vivo isomerization of the delta3-to the delta2-isomer.

N-Nitroso-1,2,3,6-tetrahydropyridine (N-nitroso-delta3-piperidine), N-nitroso-1,2,3,4-tetrahydropyridine (N-nitroso-delta2-piperidine) and N-nitroso-3,4-epoxypiperidine were tested for carcinogenicity in Fischer 344 rats. The unsaturated nitrosamines were administered in drinking water (100 mg/l). The epoxide was administered by gavage in corn oil (11.5 mg/ml, 0.2 ml twice a week). Both of the unsaturated nitrosamines were potent carcinogens (most of the animals died by the 35th week), and both produced many esophageal tumors, a property which they have in common with the parent compound, N-nitrosopiperidine. The spectrum of the other tumors formed, however, was different. The delta3-isomer produced hemangioendothelial sarcomas in the liver, which were absent in the tumor spectrum of the delta2-isomer and N-nitrosopiperidine. The delta2-isomer, on the other hand, produced tumors of the forestomach and the oropharynx, which were essentially absent in the rats treated with the delta3-isomer. N-nitroso-3,4-epoxypiperidine was a toxic compound (8 deaths in the first 5 weeks), but most of the remaining animals survived to 40 weeks. Of these, 8 animals died of induced tumors (esophagus and liver). The delta2- and the delta3-isomers were administered by gavage to groups of rats and the blood of these animals was withdrawn at timed intervals. Analysis of the serum revealed that both of the nitrosamines were cleared rapidly from circulation but that at the same time the delta3-isomer was being isomerized to the delta2. The reverse transformation did not occur in vivo.

Animals↗
PubMed2003

4-(piperidin-1-yl)pyridinium hexafluorophosphate at 150 K.

Structural characterization of the title compound, C(10)H(15)N(2)(+).PF(6)(-), shows it to be ionic, with the pyridine rather than the piperidine N atom being protonated and forming hydrogen bonds to the counter-ions, resulting in two independent ion pairs. A number of unusual features are noted, in particular the remarkably close inter-ring hydrogen contacts [1.97 (3)-2.00 (3) A] and the considerable differences in the pair of cations, in respect of the torsion angles within the piperidine ring involving the bonds to either side of the N atom.

Journal Article↗
PubMed2004

Structures of piperazine, piperidine and morpholine.

The crystal structures of piperazine, piperidine and morpholine have been determined at 150 K. All three structures are characterized by the formation of NH...N hydrogen-bonded chains. In piperazine these are linked to form sheets, but the chains are shifted so that the molecules interleave. In morpholine there are in addition weak CH...O interactions. Topological analyses show that these three structures are closely related to that of cyclohexane-II, which can be described in terms of a pseudo-cubic close-packed array of molecules in a familiar ABC layered arrangement. While the positions of the molecules within each layer are similar, hydrogen bonding occurs between the ABC layers and in order to accommodate this the molecules are rotated relative to those in cyclohexane-II. Piperidine and morpholine also adopt layered structures, with hydrogen-bonding or CH...O interactions between the layers. In these cases, however, the layering more resembles a hexagonal close-packed arrangement.

Journal Article↗
PubMed2006

SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a novel mixed nociceptin/orphanin FQ/mu-opioid receptor partial agonist: analgesic and rewarding properties in mice.

We identified a novel nociceptin/orphanin FQ (NOP)/mu-opioid receptor agonist, SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], with high binding affinity and partial agonist activity at both receptors. It was hypothesized that SR 16435 would produce antinociception and yet, unlike morphine, would have diminished rewarding properties and tolerance development. Antinociception was assessed in mice using the tail-flick assay, whereas behavioral and rewarding effects were assessed using the place conditioning (PC) paradigm. PC was established by pairing drug injections with a distinct compartment. Behavioral effects were measured after acute and repeated drug administration, and the test for PC was carried out 24 h after four drug- and vehicle-pairing sessions. SR 16435 produced an increase in tail-flick latency, but SR 16435-induced antinociception was lower than that observed with morphine. Given that naloxone blocked SR 16435-induced antinociception, it is highly likely that this effect was mediated by mu-opioid receptors. Compared with morphine, chronic SR 16435 treatment resulted in reduced development of tolerance to its antinociceptive effects. SR 16435-induced conditioned place preference (CPP) was evident, an effect that was probably mediated via mu-opioid receptors, as it was reversed by coadministration of naloxone. NOP agonist activity was also present, given that SR 16435 decreased global activity, and this effect was partially reversed with the selective NOP antagonist, SR 16430 [1-(cyclooctylmethyl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol]. Naloxone, however, also reversed the SR 16435-induced decrease in activity, indicating that both opioid and NOP receptors mediate this behavior. In summary, the mixed NOP/mu-opioid partial agonist SR 16435 exhibited both NOP and mu-opioid receptor-mediated behaviors.

Analgesics, Opioid↗
PubMed2005

Methods for the synthesis of polyhydroxylated piperidines by diastereoselective dihydroxylation: exploitation in the two-directional synthesis of aza-C-linked disaccharide derivatives.

BACKGROUND: Many polyhydroxylated piperidines are inhibitors of the oligosaccharide processing enzymes, glycosidases and glycosyltransferases. Aza-C-linked disaccharide mimetics are compounds in which saturated polyhydroxylated nitrogen and oxygen heterocycles are linked by an all-carbon tether. The saturated oxygen heterocycle has the potential to mimic the departing sugar in a glycosidase-catalysed reaction and aza-C-linked disaccharide mimetics may, therefore, be more potent inhibitors of these enzymes. RESULTS: The scope, limitations and diastereoselectivity of the dihydroxylation of stereoisomeric 2-butyl-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydro-pyridin-3-ols is discussed. In the absence of a 6-substituent on the piperidine ring, the Upjohn (cat. OsO4, NMO, acetone-water) and Donohoe (OsO4, TMEDA, CH2Cl2) conditions allow complementary diastereoselective functionalisation of the alkene of the (2R*,3R*) diastereoisomer. However, in the presence of a 6-substituent, the reaction is largely controlled by steric effects with both reagents. The most synthetically useful protocols were exploited in the two-directional synthesis of aza-C-linked disaccharide analogues. A two-directional oxidative ring expansion was used to prepare bis-enones such as (2R,6S,2'S)-6-methoxy-2-(6-methoxy-3-oxo-3,6-dihydro-2H-pyran-2-ylmethyl)-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-3-one from the corresponding difuran. Selective substitution of its N,O acetal was possible. The stereochemical outcome of a two-directional Luche reduction step was different in the two heterocyclic rings, and depended on the conformation of the ring. Finally, two-directional diastereoselective dihydroxylation yielded seven different aza-C-linked disaccharide analogues. CONCLUSION: A two-directional approach may be exploited in the synthesis of aza-C-linked disaccharide mimetics. Unlike previous approaches to similar molecules, neither of the heterocyclic rings is directly derived from a sugar, allowing mimetics with unusual configurations to be prepared. The work demonstrates that highly unsymmetrical molecules may be prepared using a two directional approach. The deprotected compounds may have potential as inhibitors of oligosaccharide-processing enzymes and as tools in chemical genetic investigations.

Journal Article↗
PubMed1983

Effects of dansyl-arginyl-(4'-ethyl)piperidine amide on gonadotropin binding to rat tissues.

The effects of dansyl-arginyl-(4'-ethyl)-piperidine amide (DAPA) on the binding of gonadotropins has been investigated. The compound inhibited the binding of hCG, human LH, and porcine LH to rat luteal membranes with an ED50 of 70 microM and the binding of human FSH to rat testicular membranes with an ED50 of 350 microM. Alteration of the substitution at the 4 carbon of the piperidine moiety altered the effect for hCG binding to luteal tissue, the ED50 being lowered with increased chain length (ED50 for H greater than methyl greater than ethyl greater than propyl = isobutyl) and shifted approximately half an order of magnitude for each carbon added. Analysis of equilibrium binding data for hCG to rat luteal membranes showed a decrease in the Ka with increasing DAPA concentrations (2.2 X 10(10), 1.0 X 10(10), and 0.4 X 10(10) M-1 for 0, 50, and 150 microM DAPA, respectively), with little or no effect on the number of sites. At a concentration of 50 microM, the compound did not affect the initial rate of association of the hormone and its receptor, but did change the dissociative behavior. After a short period of association, dissociation was followed in the absence and presence of DAPA. In all cases a biphasic dissociation was observed. The presence of DAPA slowed the rate constant for the fast phase (DAPA-treated, 4.7 X 10(-3) min-1; control, 7.6 X 10(-3) min-1) and reduced the fraction of total hCG undergoing the slow phase of dissociation (DAPA-treated, 60.6%; control, 77.4%). After a long period of association, the dissociation of hCG was monophasic, and the presence of DAPA increased the rate constant from 2.0 X 10(-4) to 4.4 X 10(-4) min-1. The results show that DAPA acted as an inhibitor of gonadotropin binding. The kinetic data suggest a sequential model of hormone binding in which the compound affected a step subsequent to the initial interaction.

Animals↗
PubMed2006

Synthesis, stereochemistry, and antimicrobial activity of 2,6-diaryl-3-(arylthio)piperidin-4-ones.

A series of novel 2,6-diaryl-3-(arylthio)piperidin-4-ones have been synthesized by reaction of arylthioacetones, substituted aromatic aldehydes, and methylamine/ammonium acetate and their structures elucidated by (1)H, (13)C, and 2D NMR (H, H-COSY, C, H-COSY, HMBC, and NOESY) spectroscopy. The NMR data reveal that all these piperidones exist in chair conformation with the 2,6-diaryl groups equatorially oriented, while the arylthio group prefers to be in either an equatorial or axial orientation depending on whether the substituent in the 2,6-diaryl rings is present in 4- or 2-position, respectively. In the case of NH-2,6-diaryl-3-(arylthio)piperidin-4-ones with o-substituted 2,6-diaryl groups, the arylthio group prefers the axial orientation presumably in a bid to minimize the steric and/or electronic repulsion. The arylthiopiperidin-4-ones exhibit significant antibacterial activity against Staphylococcus aureus, Vibrio cholerae, Salmonella typhi, and Escherichia coli and antifungal activity against Candida albicans and Aspergillus niger.

Anti-Bacterial Agents↗
PubMed1998

Synthesis and anti-microbial screening of some piperidine derivatives.

Synthesis of piperidine derivatives viz, 1-(4'-methoxy phenacyl)-N-methyl piperidinium bromide, and 1-(4'-nitrophenacyl)-N-methyl piperidinium bromide, and 1-(3', 4'-dihydroxy phenacyl)-N-methyl piperidinium chloride was carried out by quarternizing N-methyl piperidine with corresponding phenacyl halides. The structures of these compounds were elucidated by spectroscopic techniques such as UV, IR, EI mass and 1H-NMR. The compounds were subjected to antimicrobial screening in quantities of 10 mg/ml dissolved in DMSO. Disc diffusion method was used to observe the significance of these compounds against seven bacterial and one fungal cultures.

Journal Article↗
PubMedDate not supplied

[Hydrochlorides of N-hydroxyalkyl-alpha-piperidine carboxylic arylamides possessing antiarrhythmic activity].

It has been demonstrated in experimental arrhythmias of animals (aconitine one in rats, strophanthine in guinea-pigs, creation of an "ectopic focus of excitation" in cats by electric stimulation) that new compounds, the derivatives of piperidine carboxylic acids, possess antiarrhythmic activity. In doses of 6-23 mg/kg, the compounds under study prevented the development of the mixed type arrhythmia induced by intravenous injection of aconitine, prolonged the time of survival and prevented the animals' death during intravenous injection of the arrhythmogenic doses of strophanthine, prolonged the refractory period, and increased the threshold of ventricular fibrillation in cats. As regards the power of the antiarrhythmic effect, the compounds under study--hydrochlorides of arylamides of N-hydroxyalkly-alpha-piperidine carboxylic acids--approach lidocaine, yield to marcaine, and exhibit a broader range of therapeutic action.

Aconitine↗
PubMed1993

Cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1'-[2-(benzofurazan-5-yl) ethyl]-6-methanesulfonamidospiro [(2H)-1-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel class III agent.

The cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1'-[2-(benzofurazan-5-yl)ethyl]-6-methyl-sulfonamid ospiro [(2H)-1-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel spirobenzopyran piperidine class III agent, were assessed in vitro and in vivo. In ferret isolated papillary muscles, L-691,121 significantly prolonged effective refractory period (EC25 = 13 nM) and elicited a modest positive inotropic effect. In guinea pig isolated ventricular myocytes, L-691,121 prolonged action potential duration by selectively blocking (IC50 = 4.4 nM) a rapidly activating and rectifying component of the delayed rectifier K+ current, Ikr. The class III activity of L-691,121 in isolated papillary muscles was reverse frequency-dependent, and reversed by hypoxic perfusion. L-691,121 modestly depressed spontaneous beating rate (-14%) in guinea pig isolated right atria at concentrations up to 3 microM. In anesthetized dogs, the i.v. administration of 10 to 100 micrograms/kg of L-691,121 significantly increased atrial and ventricular refractoriness and prolonged the electrocardiographic Q-T interval, but did not alter atrioventricular nodal, His-Purkinje, atrial or ventricular conduction. In conscious dogs with spontaneous premature ventricular complexes at 48 hr after myocardial infarction, 10 to 1000 micrograms/kg i.v. of L-691, 121 failed to reduce premature ventricular complex frequency. However, in anesthetized dogs studied chronically (7.9 +/- 0.3 days) after infarction, 10 and 100 micrograms/kg i.v. of L-691,121 suppressed the induction of ventricular tachyarrhythmia by programmed stimulation in 8/14 (57%) and 11/14 (79%) dogs tested, respectively, and reduced the incidence of lethal ventricular arrhythmias triggered by a secondary myocardial ischemic event from 14/15 (93%) in vehicle controls to 5/14 (36%; P < .01) in L-691,121-treated (100 micrograms/kg i.v.) animals. The latter findings suggest the potential for L-691,121 to prevent the development of malignant ventricular arrhythmias in the setting of previous myocardial infarction.

Animals↗
PubMed1998

Potent sigma1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine modulates basal and N-methyl-D-aspartate-evoked nitric oxide production in vivo.

BACKGROUND AND PURPOSE: final sigma-Receptor ligands ameliorate ischemic neuronal injury and modulate neuronal responses to N-methyl-D-aspartate (NMDA) receptor stimulation. Because NMDA-evoked synthesis of nitric oxide (NO) may play an important role in excitotoxic-mediated injury, we tested the hypothesis that final sigma-receptor ligands attenuate basal and NMDA-evoked NO production in the striatum in vivo. METHODS: Microdialysis probes were placed bilaterally into the striatum of halothane-anesthetized adult Wistar rats. Rats were divided into 7 treatment groups and perfused with artificial cerebrospinal fluid (aCSF) containing 3 micromol/L [14C]L-arginine for 2 to 3 hours followed by NMDA in various combinations with the following drugs: L-nitroarginine (L-NNA); the final sigma1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective final sigma1-receptor antagonist 1-(cyclopropylmethyl)-4-(2'-oxoethyl) piperidine hydrobromide (DuP 734); and the noncompetitive NMDA receptor blocker MK-801 in aCSF. Right-left differences between [14C]L-citrulline in the effluent from rats treated with different drug combinations were assumed to reflect differences in NO production. RESULTS: After a 3-hour loading period with [14C]L-arginine, addition of 1 mmol/L NMDA increased [14C]L-citrulline recovery compared with aCSF alone. This NMDA-evoked increase was inhibited by 1 mmol/L of L-NNA and PPBP. Perfusion of 1 mmol/L of the final sigma1-receptor antagonist DuP 734 with 1 mmol/L PPBP augmented NMDA-evoked [14C]L-citrulline recovery compared with perfusion with PPBP and NMDA. MK-801 attenuated the basal as well as NMDA-evoked [14C]L-citrulline recovery. PPBP did not cause any further attenuation in the basal and NMDA-evoked [14C]L-citrulline recovery in the presence of MK-801. CONCLUSIONS: These data indicate that a final sigma1-receptor ligand attenuates basal as well as NMDA-evoked NO production. Because the attenuated NO production was reversed by DuP 734, PPBP appears to act as an agonist at the final sigma1-receptor. Attenuated NO production by final sigma1-receptor agonists provides one possible mechanism for focal ischemic neuroprotection.

Animals↗
PubMed1996

(2E,4E)-N-(4-(1H-indol-3-yl)piperidin-1-yl)alkyl-5-(substituted phenyl)-2,4-pentadienamides as antiallergic agents with antihistaminic and anti slow-reacting substance (SRS) activities.

As an extension of our study aiming to discover a novel compound with dual activities against histamine and slow-reacting substance (SRS), we synthesized two types of indolylpiperidine derivatives, 3 and 4-20. Testing for in vivo antianaphylactic activity and for in vitro anti-SRS activity revealed that (2E,4E)-5-(3,5-dimethoxy-4-hydroxyphenyl)-N-(2-(4-(1H-indol-3-yl)+ ++piperidin-1- yl)ethyl)-2,4-pentadienamide (11) exhibited potent dual activities with ED50 = 0.89 mg/kg and IC50 = 1.43 microM, respectively. However, the plasma concentration of unchanged 11 was very low when administered orally in guinea pigs. This result can be explained by fast formation of a glucuronic acid conjugate.

Amides↗
PubMed2004

Synthesis of a polymer-bound galactosylamine and its application as an immobilized chiral auxiliary in stereoselective syntheses of piperidine and amino acid derivatives.

A 2,3,4-tri-O-pivaloylated beta-D-galactopyranosyl azide bearing a hydroxy-functionalized spacer unit at the C-6 position of the galactose was synthesized and immobilized on the solid phase by using a polymer-bound chlorosilane. The azide was reduced to the corresponding galactopyranosylamine, which served as a versatile chiral auxiliary in highly diastereoselective Ugi four-component condensation reactions at ambient temperature. Fluoride-induced cleavage from the polymeric support furnished N-glycosylated N-acylated alpha-amino acid amides. The reaction of the immobilized galactosylamine with aldehydes gave rise to the corresponding aldimines, which underwent a domino Mannich-Michael condensation reaction with Danishefsky's diene at ambient temperature to yield 2-substituted 5,6-didehydropiperidin-4-ones on the solid phase. Subsequent cleavage with tetra-n-butylammonium fluoride delivered the N-glycosylated products in high yields, purities, and diastereoselectivities. A chemoselective 1,4-hydride addition to the polymer-bound dehydropiperidinones was achieved in the presence of the bulky oxygenophilic Lewis acid methylaluminum [bis(2,6-di-tert-butyl-4-methylphenoxide)]. The conjugate addition of cyano-modified Gilman reagents to the immobilized dehydropiperidinones furnished 2,6-cis-substituted piperidine derivatives as the major diastereomers that were isolated after cleavage from the support.

Amino Acids↗
PubMed2006

Dynamic kinetic resolution and desymmetrization processes: a straightforward methodology for the enantioselective synthesis of piperidines.

A straightforward procedure for the synthesis of enantiopure polysubstituted piperidines is reported. It involves the direct generation of chiral non-racemic oxazolo[3,2-a]piperidone lactams that already incorporate carbon substituents on the heterocyclic ring and the subsequent removal of the chiral auxiliary. The key step is a cyclocondensation reaction of (R)-phenylglycinol or other amino alcohols with racemic or prochiral delta-oxo (di)acid derivatives in highly stereoselective processes involving dynamic kinetic resolution and/or desymmetrization of diastereotopic or enantiotopic ester groups.

Ethanolamines↗
PubMed2005

Methyl esters of N-(dicyclohexyl)acetyl-piperidine-4-(benzylidene-4-carboxylic acids) as drugs and prodrugs: a new strategy for dual inhibition of 5 alpha-reductase type 1 and type 2.

Steroid 5alpha-reductase (5alphaR) inhibitory potency of three N-(dicyclohexyl)acetyl-piperidine-4-(benzylidene-4-carboxylic acids) and their corresponding methyl esters was monitored for type 2 isoenzyme in a benign prostatic hyperplasia cell free preparation and for type 1 isoenzyme in DU145 cells and in a cell free assay. The hydrolytic stability of the esters and their bioconversion to the corresponding acids was assessed in aqueous buffered solution (pH 7.4) and in selected biological media having measurable esterase activities. The carboxylic acids 1, 2, and 3 with high type 2 inhibitory potencies displayed only little type 1 inhibition. The esters 1a, 2a, and 3a, originally designed as prodrugs to enhance cell permeation, proved to be potent type 1 inhibitors and are therefore acting as drugs themselves. They are stable in buffered salt solution (pH 7.4), Caco-2 cells, and human plasma, whereas all esters are cleaved into the corresponding acids in benign prostatic hyperplasia tissue homogenate. Methyl esters, applied as hydrolytically stable precursor drugs to facilitate cell permeation, will yield the corresponding carboxylic acids as type 2 inhibitors after hydrolysis in the target organ. The esters themselves--stable in human plasma and Caco-2 cells--are acting as potent drugs toward 5alphaR type 1. Thus, dual inhibition of 5alphaR type 1 and type 2 can be achieved by applying a single parent compound.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗