Facile synthesis and biological evaluation of 3,3-diphenylpropanoyl piperazines as T-type calcium channel blockers

Choi, Yeon‐hee; Baek, Du Jong; Seo, Seon Hee; Lee, Jae Yeol; Pae, Ae Nim; Cho, Yong Seo; Min, Sun‐Joon

doi:10.1016/j.bmcl.2010.11.033

Cited by 14 publications

(6 citation statements)

References 25 publications

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“…During the course of this initiative, the MLSCN became the Molecular Libraries Production Center Network (MLPCN), with increased medicinal chemistry expertise to develop high quality probes for the biomedical community, of which the Vanderbilt Specialized Chemistry Center and the Johns Hopkins Ion Channel Center are members . Also during this time, the pharmaceutical industry disclosed 7 – 15 , which not only raised the bar for an impactful T-type Ca 2+ channel inhibitor probe but also required that our Centers develop a T-type Ca 2+ channel inhibitor probe free of potential IP constraints, of comparable quality to 7 – 15 , and to be freely available through the MLPCN mechanism for use by the biomedical research community. − …”

Section: Resultsmentioning

confidence: 99%

“…The majority of the second generation T-type Ca 2+ inhibitors were derived from HTS campaigns in pharmaceutical companies aimed at developing selective T-type Ca 2+ inhibitors and are covered by patents (Figure ) . Here, the major players of published efforts are Merck, inhibitor series 7 – 10 , and Korea Institute of Science and Technology, inhibitor series 11 , 13 , and 14 . − Of these, the Merck series are the most potent, possessing good DMPK profiles and in vivo activity in multiple preclinical models. Interestingly, 7 and 8 are voltage independent, while 9 displays voltage-dependent inhibition.…”

mentioning

confidence: 99%

“…Importantly, there are no reports of inhibitors selective among the Ca v 3 family (all are equipotent on Ca v 3.1, Ca v 3.2, and Ca v 3.3). While compounds 7 – 15 represent a major advance, they are covered by patents and/or published patent applications that can restrict their use by the broader biomedical research community. − …”

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confidence: 99%

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The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson’s Disease

Xiang¹,

Thompson²,

Brogan³

et al. 2011

ACS Chem. Neurosci.

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T-type Ca2+ channel inhibitors hold tremendous therapeutic potential for the treatment of pain, epilepsy, sleep disorders, essential tremor and other neurological disorders; however, a lack of truly selective tools has hindered basic research, and selective tools from the pharmaceutical industry are potentially burdened with intellectual property (IP) constraints. Thus, an MLPCN high-throughput screen (HTS) was conducted to identify novel T-type Ca2+ channel inhibitors free from IP constraints, and freely available through the MLPCN, for use by the biomedical community to study T-type Ca2+ channels. While the HTS provided numerous hits, these compounds could not be optimized to the required level of potency to be appropriate tool compounds. Therefore, a scaffold hopping approach, guided by SurflexSim, ultimately afforded ML218 (CID 45115620) a selective T-Type Ca2+ (Cav3.1, Cav3.2, Cav3.3) inhibitor (Cav3.2, IC50 = 150 nM in Ca2+ flux; Cav3.2 IC50 = 310 nM and Cav3.3 IC50 = 270 nM, respectively in patch clamp electrophysiology) with good DMPK properties, acceptable in vivo rat PK and excellent brain levels. Electrophysiology studies in subthalamic nucleus (STN) neurons demonstrated robust effects of ML218 on the inhibition of T-Type calcium current, inhibition of low threshold spike and rebound burst activity. Based on the basal ganglia circuitry in Parkinson’s disease (PD), the effects of ML218 in STN neurons suggest a therapeutic role for T-type Ca2+ channel inhibitors, and ML218 was found to be orally efficacious in haloperidol-induced catalepsy, a preclinical PD model, with comparable efficacy to an A2A antagonist, a clinically validated PD target. ML218 proves to be a powerful new probe to study T-Type Ca2+ function in vitro and in vivo, and freely available.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson’s Disease

Xiang¹,

Thompson²,

Brogan³

et al. 2011

ACS Chem. Neurosci.

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“…Diphenylpropanamides have been reported as T-type calcium channel blockers 19 and glucocorticoid receptor (GR) modulators. 20 The benzylic stereocenter is known to affect the biological activities of GR modulators.…”

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confidence: 99%

Identification of Potent and Selective Diphenylpropanamide RORγ Inhibitors

Huh

Englund

Wang

et al. 2012

ACS Med. Chem. Lett.

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Retinoic acid-related orphan receptor RORγt plays a pivotal role in the differentiation of TH17 cells. Antagonizing RORγt transcriptional activity is a potential means to treat TH17-related autoimmune diseases. Herein, we describe the identification of a series of diphenylpropanamides as novel and selective RORγ antagonists. Diphenylpropanamide 4n inhibited transcriptional activity of RORγt, but not RORα, in cells. In addition, it suppressed human TH17 cell differentiation at sub-micromolar concentrations.

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“…On the other hand, N-phenylpiperazine subunit represents one of the most varied scaffolds used in the medicinal chemistry fields [3]. The hybridization between the two groups makes very good chance for many biological activities like human adenosine A2A receptor agonists [4], selective dopamine D3 and D4 agonists [5], selective 5-HT2A receptor antagonists [6] and calcium channel blockers [7].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Crystal Structure, Density Function Theory, Molecular Docking and Antimicrobial Studies of 2-(3-(4- phenylpiperazin-1-yl) propyl) isoindoline-1,3-dione

Ghabbour¹,

Qabeel²

2016

Trop. J. Pharm Res

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Facile synthesis and biological evaluation of 3,3-diphenylpropanoyl piperazines as T-type calcium channel blockers

Cited by 14 publications

References 25 publications

The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson’s Disease

The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson’s Disease

Identification of Potent and Selective Diphenylpropanamide RORγ Inhibitors

Synthesis, Crystal Structure, Density Function Theory, Molecular Docking and Antimicrobial Studies of 2-(3-(4- phenylpiperazin-1-yl) propyl) isoindoline-1,3-dione

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