Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists

Ernst, Justin T.; Dahl, Russell; Lum, Christopher; Sebo, Lubomir; Urban, Ján; Miller, Stephen G.; Lundström, Jan O.

doi:10.1016/j.bmcl.2007.12.058

Cited by 19 publications

(15 citation statements)

References 12 publications

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“…Ernst and coworkers identified compound 17 , which contained the attractive features of reported templates, including those from maraviroc [20]. From the starting compound 17 (IC 50 = 0.97 μM), the N-ethyl spacer was elongated by one carbon to give a compound 18 which showed three fold higher potency (IC 50 = 0.31 μM).…”

Section: Medicinal Chemistry Of Maravirocmentioning

confidence: 99%

Chemokine Receptor CCR5 Antagonist Maraviroc: Medicinal Chemistry and Clinical Applications

Xu¹,

Guo²,

Wu³

2014

CTMC

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The human immunodeficiency virus (HIV) causes acquired immumodeficiency syndrome (AIDS), one of the worst global pandemic. The virus infects human CD4 T cells and macrophages, and causes CD4 depletion. HIV enters target cells through the binding of the viral envelope glycoprotein to CD4 and the chemokine coreceptor, CXCR4 or CCR5. In particular, the CCR5-utilizing viruses predominate in the blood during the disease course. CCR5 is expressed on the surface of various immune cells including macrophages, monocytes, microglia, dendric cells, and active memory CD4 T cells. In the human population, the CCR5 genomic mutation, CCR5Δ32, is associated with relative resistance to HIV. These findings paved the way for the discovery and development of CCR5 inhibitors to block HIV transmission and replication. Maraviroc, discovered as a CCR5 antagonist, is the only CCR5 inhibitor that has been approved by both US FDA and the European Medicines Agency (EMA) for treating HIV/AIDS patients. In this review, we summarize the medicinal chemistry and clinical studies of Maraviroc.

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Section: Medicinal Chemistry Of Maravirocmentioning

confidence: 99%

Chemokine Receptor CCR5 Antagonist Maraviroc: Medicinal Chemistry and Clinical Applications

Xu¹,

Guo²,

Wu³

2014

CTMC

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“…The western portion of the molecule was converted from a cyclohexylamide to a urea moiety that greatly improved anti-HIV activity. Considerable SAR led to the identification of urea 22 (Figure 4) which potently inhibited MIP-1β binding at IC 50 = 1 nM with 52% bioavailability and a terminal life of 10.7 h [88]. …”

Section: Second-generation Small-molecule Ccr5 Antagonistsmentioning

confidence: 99%

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

Kim

Giesler

Tahirovic

et al. 2016

Expert Opinion on Investigational Drugs

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Introduction The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists. Areas covered This review aims to survey the current status of ‘next generation’ CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies. Expert opinion The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests.

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“…It has been well investigated that alkyl hydrazides as an important class of effective building blocks for the preparation of nitrogenous heterocycles, especially for the synthesis of 1,2,4-triazole derivatives have caused much interest and a lot of works have been directed towards their developments [97][98][99][100][101]. Cyclization of formhydrazide with 2,3-dihydro-1H-indene thioamide 66, a product of amide with Lawesson's reagent in toluene, successfully provided triazole intermediate 67 in yield of 22% under the catalysis of mercury acetate (Scheme 25), In comparison with the relatively low yield of this compound, the final target triazole compound as the potent sodium glucose co-transporter 2 (SGLT2) inhibitor unexpectedly exhibited a highly antidiabetic activity.…”

Section: Alkyl Hydrazidesmentioning

confidence: 99%

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Zhang¹,

Damu²,

Cai³

et al. 2014

COC

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Heterocyclic 1,2,4-triazole derivatives possess unusually spacious potentiality as medicinal agents, agricultural chemicals, functional materials, ionic liquids, supramolecular catalysts as well as artificial enzymes and receptors for supramolecular recognition and biomimetic catalysis, and their various researches and developments have been being a quite rapidly developing and active highlight topic with an infinite space. Numerous efforts have been directed toward various types of possible applications of 1,2,4-triazole-based compounds and a lot of important progress has been made, especially their preparations have attracted increasing attention. This review systematically summarized the recent advances in the syntheses of 1,2,4-triazole derivatives, including: (1) Cyclizations to form triazole ring; (2) Transformations of heterocyclic compounds to construct triazole ring; (3) Substitutions on 1,2,4-triazole ring; (4) Structural modifications in side chains of 1,2,4-triazole ring. It was hoped that this review would be helpful for the design and development of highly efficient preparation of 1,2,4-triazole derivatives with various sorts and varieties of extensively potential applications in medicine, agriculture, chemistry, materials, supramolecular sciences and so on.

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Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists

Cited by 19 publications

References 12 publications

Chemokine Receptor CCR5 Antagonist Maraviroc: Medicinal Chemistry and Clinical Applications

Chemokine Receptor CCR5 Antagonist Maraviroc: Medicinal Chemistry and Clinical Applications

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

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