PMID- 16251299
OWN - NLM
STAT- MEDLINE
DCOM- 20060118
LR  - 20201209
IS  - 0066-4804 (Print)
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Linking)
VI  - 49
IP  - 11
DP  - 2005 Nov
TI  - TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in 
      vitro and has favorable pharmacokinetics in humans.
PG  - 4584-91
AB  - The first small-molecule CCR5 antagonist, TAK-779, could not be developed as an 
      anti-human immunodeficiency virus type (anti-HIV-1) agent because of its poor 
      oral bioavailability. TAK-652 is an orally bioavailable TAK-779 derivative with 
      potent anti-HIV-1 activity. TAK-652 inhibited the binding of RANTES (regulated on 
      activation, normal T-cell expressed and secreted), macrophage inflammatory 
      protein 1alpha (MIP-1alpha), and MIP-1beta to CCR5-expressing cells at nanomolar 
      concentrations. TAK-652 could also suppress the binding of monocyte chemotactic 
      protein 1 (MCP-1) to CCR2b-expressing cells. However, its inhibitory effect on 
      ligand binding to other chemokine receptors was limited. TAK-652 was active 
      against CCR5-using (R5) HIV-1 but totally inactive against CXCR4-using (X4) 
      HIV-1. The compound was active against R5 HIV-1 clinical isolates containing 
      reverse transcriptase and protease inhibitor-resistant mutations, with a mean 50% 
      effective concentration (EC50) and EC90 of 0.061 and 0.25 nM, respectively. In 
      addition, recombinant R5 viruses carrying different subtype (A to G) envelope 
      proteins were equally susceptible to TAK-652. A single oral administration of 
      TAK-652 up to 100 mg was safe and well tolerated in humans. The compound 
      displayed favorable pharmacokinetics, and its plasma concentration was 7.2 ng/ml 
      (9.1 nM) even 24 h after the administration of 25 mg. Thus, TAK-652 is a 
      promising candidate as a novel entry inhibitor of HIV-1.
FAU - Baba, Masanori
AU  - Baba M
AD  - Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate 
      School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, 
      Kagoshima 890-8544, Japan. baba@m.kufm.kagoshima-u.ac.jp
FAU - Takashima, Katsunori
AU  - Takashima K
FAU - Miyake, Hiroshi
AU  - Miyake H
FAU - Kanzaki, Naoyuki
AU  - Kanzaki N
FAU - Teshima, Koichiro
AU  - Teshima K
FAU - Wang, Xin
AU  - Wang X
FAU - Shiraishi, Mitsuru
AU  - Shiraishi M
FAU - Iizawa, Yuji
AU  - Iizawa Y
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Anti-HIV Agents)
RN  - 0 (CCR5 Receptor Antagonists)
RN  - 0 (Chemokine CCL3)
RN  - 0 (Chemokine CCL4)
RN  - 0 (Chemokine CCL5)
RN  - 0 (Imidazoles)
RN  - 0 (Macrophage Inflammatory Proteins)
RN  - 0 (Receptors, CCR5)
RN  - 0 (Sulfoxides)
RN  - 15C116UA4Y (cenicriviroc)
SB  - IM
MH  - Animals
MH  - Anti-HIV Agents/adverse effects/pharmacokinetics/*pharmacology
MH  - *CCR5 Receptor Antagonists
MH  - CHO Cells
MH  - Chemokine CCL3
MH  - Chemokine CCL4
MH  - Chemokine CCL5/metabolism
MH  - Cricetinae
MH  - Double-Blind Method
MH  - HIV-1/*drug effects
MH  - HeLa Cells
MH  - Humans
MH  - Imidazoles/adverse effects/pharmacokinetics/*pharmacology
MH  - Leukocytes, Mononuclear/virology
MH  - Macrophage Inflammatory Proteins/metabolism
MH  - Membrane Fusion/drug effects
MH  - Receptors, CCR5/physiology
MH  - Sulfoxides
PMC - PMC1280155
EDAT- 2005/10/28 09:00
MHDA- 2006/01/19 09:00
PMCR- 2005/11/01
CRDT- 2005/10/28 09:00
PHST- 2005/10/28 09:00 [pubmed]
PHST- 2006/01/19 09:00 [medline]
PHST- 2005/10/28 09:00 [entrez]
PHST- 2005/11/01 00:00 [pmc-release]
AID - 49/11/4584 [pii]
AID - 0733-05 [pii]
AID - 10.1128/AAC.49.11.4584-4591.2005 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2005 Nov;49(11):4584-91. doi: 
      10.1128/AAC.49.11.4584-4591.2005.