Discovery of a Piperidine-4-carboxamide CCR5 Antagonist (TAK-220) with Highly Potent Anti-HIV-1 Activity

Imamura, Shinichi; Ichikawa, Takashi; Nishikawa, Yoshinori; Kanzaki, Naoyuki; Takashima, Katsunori; Niwa, Shin‐Ichi; Iizawa, Yuji; Baba, Masanori; Sugihara, Yoshihiro

doi:10.1021/jm051034q

Cited by 66 publications

(46 citation statements)

References 20 publications

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“…For CCR5 antagonists SCH-C (Palani et al, 2002), VVC (SCH-D; Strizki et al, 2005), maraviroc (MVC; Wood and Armour, 2005), aplaviroc (APL; Watson et al, 2005), TAK-779 (Baba et al, 1999), and TAK-220 (Imamura et al, 2006;Seto et al, 2006) please refer to their respective publications.…”

Section: Reagentsmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Kondru

Zhang²,

Ji³

et al. 2007

Mol Pharmacol

174

189

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In addition to being an important receptor in leukocyte activation and mobilization, CCR5 is the essential coreceptor for human immunodeficiency virus (HIV). A large number of smallmolecule CCR5 antagonists have been reported that show potent activities in blocking chemokine function and HIV entry. To facilitate the design and development of next generation CCR5 antagonists, docking models for major classes of CCR5 antagonists were created by using site-directed mutagenesis and CCR5 homology modeling. Five clinical candidates: maraviroc, vicriviroc, aplaviroc, TAK-779, and TAK-220 were used to establish the nature of the binding pocket in CCR5. Although the five antagonists are very different in structure, shape, and electrostatic potential, they were able to fit in the same binding pocket formed by the transmembrane (TM) domains of CCR5. It is noteworthy that each antagonist displayed a unique interaction profile with amino acids lining the pocket. Except for TAK-779, all antagonists showed strong interaction with Glu283 in TM 7 via their central basic nitrogen. The fully mapped binding pocket of CCR5 is being used for structure-based design and lead optimization of novel anti-HIV CCR5 inhibitors with improved potency and better resistance profile.Human immunodeficiency virus (HIV) enters the host cell via the interaction of the viral envelope protein gp160 and the receptor/coreceptors on host cell surface. The majority of primary HIV-1 strains use CCR5 as coreceptor (termed R5 virus), whereas some viruses are able to use another chemokine receptor, CXCR4, as coreceptor (termed X4 virus) or use both CCR5 and CXCR4 as coreceptors (termed R5X4 virus). Because CCR5 is the predominant coreceptor for clinical HIV isolates, and the normal physiology within the human genetic knockout population, CCR5 has become a very attractive target for anti-HIV therapy. A number of small molecule CCR5 antagonists have been identified that demonstrated potent antiviral effects both in cell culture and in clinical trials.TAK-779, a quaternary ammonium anilide, was the first small molecule CCR5 antagonist reported (Baba et al., 1999). This compound was terminated as a result of poor oral availability. Two structurally diverse followers TAK-220 and TAK-652 are both in clinical trials (Imamura et al., 2006;Seto et al., 2006). Several other small molecule CCR5 antagonists with good potency and/or pharmacological properties have also been reported by other pharmaceutical companies. These include SCH-C (SCH-351125), vicriviroc (VVC, SCH-D, SCH-417690), aplaviroc (APL, AK602, GW873140), and maraviroc (MVC, UK-427,857). SCH-C is an oximino-piperidino-piperidine amide (Palani et al., 2002) that showed potent antiviral activity in vivo. However, its clinical development was terminated as a result of HERG inhibitory activity. SCH-D is the next generation compound of SCH-C, which is in late stage clinical development. SCH-D showed better oral availability, potency, safety, and pharmacological properties than SCH-C Article, publication d...

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Section: Reagentsmentioning

confidence: 99%

“…This compound was terminated as a result of poor oral availability. Two structurally diverse followers TAK-220 and TAK-652 are both in clinical trials (Imamura et al, 2006;Seto et al, 2006). Several other small molecule CCR5 antagonists with good potency and/or pharmacological properties have also been reported by other pharmaceutical companies.…”

mentioning

confidence: 99%

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Kondru

Zhang²,

Ji³

et al. 2007

Mol Pharmacol

174

189

View full text Add to dashboard Cite

show abstract

“…Further studies by Takeda scientists led to the discovery of the piperidine-4-carboxamide TAK-220 (20 Fig. 6), which had nanomolar affinity for CCR5 and was a potent inhibitor of the replication of clinical isolates of HIV-1 [188]. Subsequent development of TAK-220 leads to the derivative TAK-652 (21 Fig.…”

Section: Inhibiting Viral Entry Via Ccr5 and Cxcr4mentioning

confidence: 99%

Chemokine Receptors in Allergy, Inflammation, and Infectious Disease

Pease

Horuk

2014

Topics in Medicinal Chemistry

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Chemokines play an important role in disease by virtue of their effects on immune cells. They mediate their biological effects by acting on G-proteincoupled receptors, which represent one of the most druggable classes of proteins. In this review we will examine the role of chemokines in autoimmunity and inflammation by concentrating on the part they play in the pathophysiology of several diseases including asthma, multiple sclerosis, and rheumatoid arthritis. We will describe the various strategies that pharmaceutical companies have come up with to block the effect of chemokines in driving these disease processes and how they have fared in the clinic. We will also briefly discuss the repurposing of chemokine receptor antagonists in new indications.

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“…3C) (Seto et al, 2006) and TAK-220 (Fig. 3D) Imamura et al, 2006), of which both are orally available as subnanomolar anti-HIV-1 inhibitors. TAK-652 resistant virus emerged through in vitro selection shows cross-resistance to TAK-779 but remains sensitive to TAK-220 (Baba et al, 2007).…”

Section: Small Molecule Entry Inhibitorsmentioning

confidence: 99%

Closing the door to human immunodeficiency virus

2013

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The pandemic of human immunodeficiency virus type one (HIV-1), the major etiologic agent of acquired immunodeficiency disease (AIDS), has led to over 33 million people living with the virus, among which 18 million are women and children. Until now, there is neither an effective vaccine nor a therapeutic cure despite over 30 years of efforts. Although the Thai RV144 vaccine trial has demonstrated an efficacy of 31.2%, an effective vaccine will likely rely on a breakthrough discovery of immunogens to elicit broadly reactive neutralizing antibodies, which may take years to achieve. Therefore, there is an urgency of exploring other prophylactic strategies. Recently, antiretroviral treatment as prevention is an exciting area of progress in HIV-1 research. Although effective, the implementation of such strategy faces great financial, political and social challenges in heavily affected regions such as developing countries where drug resistant viruses have already been found with growing incidence. Activating latently infected cells for therapeutic cure is another area of challenge. Since it is greatly difficult to eradicate HIV-1 after the establishment of viral latency, it is necessary to investigate strategies that may close the door to HIV-1. Here, we review studies on non-vaccine strategies in targeting viral entry, which may have critical implications for HIV-1 prevention.

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Discovery of a Piperidine-4-carboxamide CCR5 Antagonist (TAK-220) with Highly Potent Anti-HIV-1 Activity

Cited by 66 publications

References 20 publications

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Chemokine Receptors in Allergy, Inflammation, and Infectious Disease

Closing the door to human immunodeficiency virus

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