The discovery of tropane-derived CCR5 receptor antagonists

被引：14

作者：

Armour, DR ^{[1
]}

de Groot, MJ ^{[1
]}

Price, DA ^{[1
]}

Stammen, BLC ^{[1
]}

Wood, A ^{[1
]}

Perros, M ^{[1
]}

Burt, C ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Sandwich CT13 9NJ, Kent, England

来源：

CHEMICAL BIOLOGY & DRUG DESIGN | 2006年 / 67卷 / 04期

关键词：

antiviral; benzimidazole; CCR5; antagonists; human immunodeficiency virus; tropane;

D O I：

10.1111/j.1747-0285.2006.00376.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.

引用

页码：305 / 308

页数：4

共 11 条

[1] Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1 alpha, MIP-1 beta, and RANTES [J].

Combadiere, C ;

Ahuja, SK ;

Tiffany, HL ;

Murphy, PM .

JOURNAL OF LEUKOCYTE BIOLOGY, 1996, 60 (01) :147-152

[2] Novel approach to predicting P450-mediated drug metabolism: Development of a combined protein and pharmacophore model for CYP2D6 [J].

de Groot, MJ ;

Ackland, MJ ;

Horne, VA ;

Alex, AA ;

Jones, BC .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (09) :1515-1524

[3] The impact of drug-induced qt interval prolongation on drug discovery and development [J].

Fermini, B ;

Fossa, AA .

NATURE REVIEWS DRUG DISCOVERY, 2003, 2 (06) :439-447

[4]

Hoffmann RW, 2000, ANGEW CHEM INT EDIT, V39, P2054, DOI 10.1002/1521-3773(20000616)39:12<2054::AID-ANIE2054>3.3.CO

[5]

2-Q

[6] Molecular and cellular mechanisms of cardiac arrhythmias [J].

Keating, MT ;

Sanguinetti, MC .

CELL, 2001, 104 (04) :569-580

[7] The current status of, and challenges in, the development of CCR5 inhibitors as therapeutics for HIV-1 infection [J].

Maeda, K ;

Nakata, H ;

Ogata, H ;

Koh, Y ;

Miyakawa, T ;

Mitsuya, H .

CURRENT OPINION IN PHARMACOLOGY, 2004, 4 (05) :447-452

[8] Twenty years of therapy for HIV-1 infection [J].

Pomerantz, RJ ;

Horn, DL .

NATURE MEDICINE, 2003, 9 (07) :867-873

[9] A synthesis of tropinone. [J].

Robinson, R .

JOURNAL OF THE CHEMICAL SOCIETY, 1917, 111 :762-768

[10] SUBSTRATE INTERACTION WITH CYTOCHROME-P-450 [J].

SCHENKMAN, JB ;

SLIGAR, SG ;

CINTI, DL .

PHARMACOLOGY & THERAPEUTICS, 1981, 12 (01) :43-71

← 1 2 →