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

Streiber, Martina; Picard, Franck; Scherer, Christiane; Seidel, Stefanie; Hartmann, Rolf W.

doi:10.1002/jps.20265

Cited by 9 publications

(12 citation statements)

References 28 publications

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“…1A) to shield the negative charge of the carboxylic acid group of SPI-112 (Fig 1A). The methyl ester analog is predicted to be hydrolyzed to the corresponding carboxylic acid by cellular esterases upon entry into cells similar to other methyl ester prodrugs [43, 44]. In vitro Shp2 PTP inhibition assay showed that, while SPI-112 potently inhibited Shp2 PTP (IC 50 : 1.0 µM) as reported previously [9], the methyl ester analog did not inhibit Shp2 PTP (IC 50 > 100 µM) (Fig.…”

Section: Resultssupporting

confidence: 68%

Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112

Chen

Pernazza

Scott

et al. 2010

Biochemical Pharmacology

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The protein tyrosine phosphatase (PTP) Shp2 (PTPN11) is an attractive target for anticancer drug discovery because it mediates growth factor signaling and its gain-of-function mutants are causally linked to leukemias. We previously synthesized SPI-112 from a lead compound of Shp2 inhibitor, NSC-117199. In this study, we demonstrated that SPI-112 bound to Shp2 by surface plasmon resonance (SPR) and displayed competitive inhibitor kinetics to Shp2. Like some other compounds in the PTP inhibitor discovery efforts, SPI-112 was not cell permeable, precluding its use in biological studies. To overcome the cell permeation issue, we prepared a methyl ester SPI-112 analog (SPI-112Me) that is predicted to be hydrolyzed to SPI-112 upon entry into cells. Fluorescence uptake assay and confocal imaging suggested that SPI-112Me was taken up by cells. Incubation of cells with SPI-112Me inhibited epidermal growth factor (EGF)-stimulated Shp2 PTP activity and Shp2-mediated paxillin dephosphorylation, Erk1/2 activation, and cell migration. SPI-112Me treatment also inhibited Erk1/2 activation by a Gab1-Shp2 chimera. Treatment of Shp2E76K mutant-transformed TF-1 myeloid cells with SPI-112Me resulted in inhibition of Shp2E76K-dependent cell survival, which is associated with inhibition of Shp2E76K PTP activity, Shp2E76K-induced Erk1/2 activation, and Bcl-XL expression. Furthermore, SPI-112Me enhanced interferon-γ (IFN-γ)-stimulated STAT1 tyrosine phosphorylation, ISRE-luciferase reporter activity, p21 expression, and the anti-proliferative effect. Thus, the SPI-112 methyl ester analog was able to inhibit cellular Shp2 PTP activity.

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Section: Resultssupporting

confidence: 68%

Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112

Chen

Pernazza

Scott

et al. 2010

Biochemical Pharmacology

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“…Human embryonic kidney cells recombinantly expressing 5-α-reductase isoenzyme type I 10 were cultivated at 37°C in Dulbecco’s Modified Eagle’s Medium (pH 7.4) supplemented with 10% fetal calf serum, penicillin/streptomycin (100 U/mL and 100 μg/mL), and 0.5 mg/mL of Geneticin-418-sulfate in a humidified 5% CO 2 atmosphere. The assay was conducted basically as described, 11 with minor modifications.…”

Section: Methodsmentioning

confidence: 99%

Effect of the multifunctional cosmetic ingredient sphinganine on hair loss in men and women with diffuse hair reduction

Gerlach¹,

Mentel²,

Köhler³

et al. 2016

CCID

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Sphingolipids are well known to promote keratinocyte differentiation and to induce ceramide production. In addition, they show anti-inflammatory and antimicrobial activities. Thus, the aim of this study is to investigate the potential effect of sphinganine on prolonging the hair anagen rate and improving the overall hair quality and scalp health. The inhibitory potential of sphinganine toward 5-α-reductase was studied using an in vitro assay. The stimulation of the antimicrobial peptide HBD2 by sphinganine was measured by real-time polymerase chain reaction and immunostaining. Sphinganine bioavailability was studied ex vivo using a pig skin model. A placebo-controlled, double-blind study was designed to evaluate the efficacy of sphinganine on hair loss and hair/scalp quality in vivo. In vitro results showed that sphinganine is a potent inhibitor of 5-α-reductase type I that prevents the conversion of testosterone to dihydrotestosterone, a key factor of androgenetic male baldness. In vivo results demonstrated efficacy in reducing non-illness-related hair loss among males. In terms of expert rating, all hair quality and scalp parameters improved after application of sphinganine. Improved scalp health might be linked to the observed increase of the antimicrobial peptide HBD2. Thus, sphinganine is well suited as a topical alternative for the improvement of scalp health and hair quality and anti-hair loss application.

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“…These properties of esters (75, 76, 78) opened a new therapeutic strategy for dual inhibition of 5αR type 1 and 2 proposed by Hartmann et al [78] (Fig. (36)), ( Table 1).…”

Section: Carboxylic Acidsmentioning

confidence: 95%

“…Carboxylic acids (69, 70 and 77) exhibited good type 2 potency and weak inhibitory potency towards type 1 5αR isoenzyme. Surprisingly, corresponding methyl esters (75,76,78) showed weak-to-mediocre inhibitory potencies toward type 2 Structural modifications of active inhibitors (compounds 67 -69) led to the discovery of the most potent inhibitors of isozyme of type 2. In the dicyclohexylacetyl series the introduction of fluorine substituent at the benzene ring (70), exchange of the carboxy group for a carboxymethyl moiety (71), and combination of both structural modifications (72) Fig.…”

Section: Carboxylic Acidsmentioning

confidence: 99%

“…The incrase in activity observed for the exchange of the carboxy group for a carboxymethyl moiety indicated that the protein shows some conformational flexibility in this part of the active site. As continuation of these studies the methyl esters (75,76,78) of series of N-substituted 4-benzylidenepiperidine-4'-carboxylic acid (69,70,77) were investigated as potential pro-drugs of 5α reductase inhibitors [71]. Carboxylic acids (69, 70 and 77) exhibited good type 2 potency and weak inhibitory potency towards type 1 5αR isoenzyme.…”

Section: Carboxylic Acidsmentioning

confidence: 99%

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Trends in the Development of New Drugs for Treatment of Benign Prostatic Hyperplasia

Kulig¹,

Malawska

2006

CMC

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Benign prostatic hyperplasia (BPH) is a common condition in aging men that is characterized by nonmalignant enlargement of the prostate gland, and is frequently accompanied by urinary obstruction, and lower urinary tract symptoms (LUST). Currently pharmacotherapy of BPH is based on two classes of drugs: alpha(1)-adrenoceptor (alpha(1)-AR) antagonists and 5alpha-reductase inhibitors. It has been shown that alpha(1)-AR antagonists reduce symptom scores and increase peak urinary flow rates in BPH. Of particular importance for BPH therapy are uroselective alpha(1)-AR antagonists for which the hypotensive related side-effect caused by alpha(1)-AR blockade is reduced. 5alpha-Reductase inhibitors reduce prostate volume and symptom scores, while increasing peak urinary flow rates. This review describes new alpha(1)-AR antagonists and 5alpha-reductase inhibitors in the treatment of BPH. The new alpha(1)-AR antagonists represent various structures such as quinazolines, phenylethylamines, piperidines, and arylpiperazines. 5alpha-Reductase inhibitors are classified into two groups: steroidal and non-steroidal. The newer non-steroidal inhibitors include derivatives of benzo[c]quinolizinones, benzo[f]quinolonones, piperidones and carboxylic acids. Besides the development of new compounds belonging to the above mentioned groups, new agents for BPH treatment are sought among combined 5alpha-reductase/alpha(1)-AR inhibitors, endothelins, androgen receptors antagonists, growth factors, estrogens and phosphodiesterase isoenzymes as well as several phytomedicines, used for prevention and treatment of prostate disorders. These new agents can be used for the design of future targets and development of new drugs in the treatment of BPH. The discovery of a number of active leads may also ultimately help in developing new safe and effective drugs.

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

Cited by 9 publications

References 28 publications

Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112

Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112

Effect of the multifunctional cosmetic ingredient sphinganine on hair loss in men and women with diffuse hair reduction

Trends in the Development of New Drugs for Treatment of Benign Prostatic Hyperplasia

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