- Design, synthesis, and antibacterial evaluation of novel derivatives of NPS-2143 for the treatment of methicillin-resistant S. aureus (MRSA) infection
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Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant global health challenge due to the emergence of strains exhibiting resistance to nearly all classes of antibiotics. This necessitates the rapid development of novel antimicrobials to circumvent this critical problem. Screening of compounds based on phenotypes is one of the major strategies for finding new antibiotics at present. Hence, we here performed a phenotypic screening against MRSA and identified NPS-2143 exhibiting activity against MRSA with an MIC value of 16 μg ml?1. In order to discover more potent anti-MRSA agents, a series of derivatives of NPS-2143 were designed and synthesized. The most promising compounds 48 and 49 exhibited favorable antimicrobial activity with an MIC value of 2 μg ml?1.
- Chen, Yao,Ju, Yuan,Li, Chungen,Yang, Tao,Deng, Yong,Luo, Youfu
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p. 545 - 554
(2019/04/10)
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- Synthesis of the calcilytic ligand NPS 2143
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(R)-3 (NPS 2143) is a negative allosteric modulator of the human calcium-sensing receptor (CaSR) and as such represents an important pharmacological tool compound for studying the CaSR. Herein, we disclose for the first time a complete experimental description, detailed characterisation and assessment of enantiomeric purity for (R)-3. An efficient, reproducible and scalable synthesis of (R)-3 that requires a minimum of chromatographic purification steps is presented. (R)-3 was obtained in excellent optical purity (er > 99:1) as demonstrated by chiral HPLC and the pharmacological profile for (R)-3 is in full accordance with that reported in the literature.
- Johansson, Henrik,Cailly, Thomas,Thomsen, Alex Rojas Bie,Braeuner-Osborne, Hans,Pedersen, Daniel Sejer
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p. 1383 - 1387
(2013/08/23)
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- Antagonists of the calcium receptor I. Amino alcohol-based parathyroid hormone secretagogues
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Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC50 = 11 μM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the β-adrenergic receptor subtypes. These SAR studies ultimately led to the identification of 38 (NPS 2143; SB-262470A), a potent and orally active CaR antagonist. Pharmacokinetic characterization of 38 in the rat revealed that this molecule had a large volume of distribution (11 L/kg), which resulted in a prolonged systemic exposure, protracted increases in the plasma levels of PTH, and an overall lack of net bone formation effect in a rodent model of osteoporosis.
- Marquis, Robert W.,Lago, Amparo M.,Callahan, James F.,Lee Trout, Robert E.,Gowen, Maxine,DelMar, Eric G.,Van Wagenen, Bradford C.,Logan, Sarah,Shimizu, Scott,Fox, John,Nemeth, Edward F.,Yang, Zheng,Roethke, Theresa,Smith, Brian R.,Ward, Keith W.,Lee, John,Keenan, Richard M.,Bhatnagar, Pradip
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experimental part
p. 3982 - 3993
(2009/12/28)
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- Chemoenzymatic synthesis of calcilytic agent NPS-2143 employing a lipase-mediated resolution protocol
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The kinetic resolution of chlorohydrin (±)-6 has been successfully carried out via a lipase-mediated transesterification with vinyl acetate in organic as well as ionic liquid media to yield (R)-alcohol 6 and (S)-acetate 7 in high enantioselectivity. An en
- Kamal, Ahmed,Chouhan, Gagan
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p. 2784 - 2789
(2007/10/03)
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- Discovery and structure-activity relationships of 2-benzylpyrrolidine- substituted aryloxypropanols as calcium-sensing receptor antagonists
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A structure-activity relationship study of the amine portion of the calcilytic compound NPS-2143 resulted in the discovery of substituted 2-benzylpyrrolidines as replacements for the 1,1-dimethyl-2-naphthalen-2-yl- ethylamine. When compared to NPS-2143, a
- Yang, Wu,Wang, Yufeng,Roberge, Jacques Y.,Ma, Zhengping,Liu, Yalei,Lawrence, R. Michael,Rotella, David P.,Seethala, Ramakrishna,Feyen, Jean H. M.,Dickson Jr., John K.
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p. 1225 - 1228
(2007/10/03)
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- SUBSTITUTED PIPERODINES AND PYRROLIDINES AS CALCIUM SENSING RECEPTOR MODULATORS AND METHOD
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Compounds are provided which are antagonists of the calcium sensing receptor, and have the general formula (I) wherein m is 0, 1, 2, 3 or 4; each X is independently selected from the group consisting of hydrogen, halo, cyano, nitro, OCF3, hydroxy, amino,
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