Phenylpyazoleanilides as Potent Inhibitor of IL-15 Dependent T Cell Proliferation. Part 2: Discovery of a New Drug Candidate, Y-320

Author(s):

Hiroyuki Ushio, Seigo Ishibuchi, Kunitomo Adachi, Kouichi Oshita and Kenji ChibaPages 292-296 (5)

Abstract:

Through the optimization of the active metabolite 2 of the piperidine derivative 1, we discovered a potent new drug candidate for the treatment of RA, Y-320 that inhibits T cell activation induced by IL-15 and shows a therapeutic effect on collagen-induced arthritis in DBA/1J mice. Design and structure-activity relationships are described.

Keywords:

Y-320, IL-15, Phenylpyrazoleanilide, RA, CIA

Affiliation:

Medicinal Chemistry Laboratory,Research division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.

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Synthesis and Biological Evaluation of Spiro-δ-lactones as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 2 (17β-HSD2)

Author(s):

Kuiying Xu, Marie Wetzel, Rolf W. Hartmann and Sandrine Marchais-OberwinklerPages 406-421 (16)

Abstract:

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyzes the oxidation of the potent estradiol (E2) to the less active estrogen estrone (E1). Inhibitors of this enzyme should maintain the local level of E2 in bone tissue when the E2 concentration in the circulation drops and therefore might be useful for the treatment of osteoporosis. In this work, novel non-steroidal spiro-δ-lactone compounds designed as 17β-HSD2 inhibitors were synthesized and their physicochemical and biological properties were investigated. These new spiro-δ-lactones are not sufficiently stable for further development and show low inhibition of the enzyme.

Keywords:

17β-hydroxysteroid dehydrogenase type 2 inhibitors, Drug design, Osteoporosis, Spiro-δ-lactones, Steroidomimetics, Biological Evaluation, Spiro-lactones, Inhibitors, 17-Hydroxysteroid, Dehydrogenase, SDRs, dihydrotestosterone, 4-androstene-3,17-dione, spirolactone derivatives, aromatase inhibitors

Affiliation:

Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123Saarbrucken, Germany.

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Design and Synthesis of New Dual Binding Site Cholinesterase Inhibitors: in vitro Inhibition Studies with in silico Docking

Author(s):

Muhammad Yar, Marek Bajda, Rana Atif Mehmood, Lala Rukh Sidra, Nisar Ullah, Lubna Shahzadi, Muhammad Ashraf, Tayaba Ismail, Sohail Anjum Shahzad, Zulfiqar Ali Khan, Syed Ali Raza Naqvi and Nasir MahmoodPages 331-338 (8)

Abstract:

Cholinesterases (ChEs) play a vital role in the regulation of cholinergic transmission. The inhibition of ChEs is considered to be involved in increasing acetylcholine level in the brain and thus has been implicated in the treatment of Alzheimer’s disease. We have designed and synthesized a series of novel indole derivatives and screened them for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of the tested compounds exhibited inhibitory activity against AChE and BChE. Among them 4f and 6e showed the highest AChE inhibitory activity with IC50 91.21±0.06 and 68.52±0.04 µM, respectively. However compound 5a exhibited the highest inhibitory activity against BChE (IC50 55.21±0.12 µM).

Keywords:

Acetylcholinesterase, Alzheimer’s disease, Butyrylcholinesterase, Hydrazides, Indole derivatives, Molecular docking, SAR.

Affiliation:

Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information Technology, Lahore, 54000, Pakistan.

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4-Substituted-2-Methoxyphenol: Suitable Building Block to Prepare New Bioactive Natural-like Hydroxylated Biphenyls

Author(s):

Maria Antonietta Dettori, Davide Fabbri, Marina Pisano, Carla Rozzo, Giuseppe Palmieri, Alessandro Dessi, Roberto Dallocchio and Giovanna DeloguPages 131-139 (9)

Abstract:

A small collection of eugenol- and curcumin-analog hydroxylated biphenyls was prepared by straightforward methods starting from natural 4-substituted-2-methoxyphenols and their antitumoral activity was evaluated in vitro. Two curcumin-biphenyl derivatives showed interesting growth inhibitory activities on different malignant melanoma cell lines with IC50 ranging from 13 to 1 µ M. Preliminary molecular modeling studies were carried out to evaluate conformations and dihedral angles suitable for antiproliferative activity in hydroxylated biphenyls bearing a side aliphatic chain.

Keywords:

Curcumin, dihedral angle, hydroxylated biphenyls, malignant melanoma, synthesis.

Affiliation:

CNR-Istituto di Chimica Biomolecolare, UOS Sassari, Traversa La Crucca 3, 07100 Sassari-Baldinca Italy.

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Potent and Orally Bioavailable Antiplatelet Agent, PLD-301, with the Potential of Overcoming Clopidogrel Resistance

Author(s):

Jingyu Chen and Michael Zhiyan WangPages 250-254 (5)

Abstract:

PLD-301, a phosphate prodrug of clopidogrel thiolactone discovered by Prelude Pharmaceuticals with the aim to overcome clopidogrel resistance, was evaluated for its in vivo inhibitory effect on ADP-induced platelet aggregation in rats. The potency of PLD-301 was similar to that of prasugrel, but much higher than that of clopidogrel. The results of pharmacokinetic analysis showed that the oral bioavailability of clopidogrel thiolactone converted from PLD-301 was 4- to 5-fold higher than that of the one converted from clopidogrel, suggesting that in comparison with clopidogrel, lower doses of PLD-301 could be used clinically. In summary, PLD-301 presents a potent and orally bioavailable antiplatelet agent that might have some advantages over clopidogrel, such as overcoming clopidogrel resistance for CYP2C19-allele loss-of-function carriers, and lowering dose-related toxicity due to a much lower effective dose.

Keywords:

Clopidogrel, active metabolite, drug resistance, platelet ADP receptor, platelet aggregation, thrombosis.

Affiliation:

Prelude Pharmaceuticals, 99 14th KeChuang Street, Building 33, Suite D-601, Beijing Economic- Technological Development Area, Beijing 101111, China.

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