Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application

被引：10

作者：

Kesteleyn, Bart ^{[1
]}

Amssoms, Katie ^{[1
]}

Schepens, Wim ^{[1
]}

Hache, Geerwin ^{[1
]}

Verschueren, Wim ^{[1
]}

Van De Vreken, Wim ^{[1
]}

Rombauts, Klara ^{[1
]}

Meurs, Greet ^{[1
]}

Sterkens, Patrick ^{[1
]}

Stoops, Bart ^{[1
]}

Baert, Lieven ^{[1
]}

Austin, Nigel ^{[1
]}

Wegner, Jorg ^{[1
]}

Masungi, Chantal ^{[1
]}

Dierynck, Inge ^{[1
]}

Lundgren, Stina ^{[2
]}

Jonsson, Daniel ^{[2
]}

Parkes, Kevin ^{[2
]}

Kalayanov, Genadiy ^{[2
]}

Wallberg, Hans ^{[2
]}

Rosenquist, Asa ^{[2
]}

Samuelsson, Bertil ^{[2
]}

Van Emelen, Kristof ^{[1
]}

Thuring, Jan Willem ^{[1
]}

机构：

[1] Janssen Infect Dis, B-2340 Beerse, Belgium

[2] Medivir AB, SE-14122 Huddinge, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 01期

关键词：

HIV/AIDS; HIV Protease; Protease inhibitor; Long-acting formulation; Nanosuspension; HUMAN-IMMUNODEFICIENCY-VIRUS; HYDROXYETHYLENE DIPEPTIDE ISOSTERES; POTENT; THERAPY; ANALOGS;

D O I：

10.1016/j.bmcl.2012.10.095

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design and synthesis of novel HIV-1 protease inhibitors (PIs) (1-22), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was initiated from compound 1, a Phe-Phe hydroxyethylene peptidomimetic PI, and was directed towards the discovery of new PIs suitable for a long-acting (LA) injectable drug application. Introducing a heterocyclic 6-methoxy-3-pyridinyl or a 6-(dimethylamino)-3-pyridinyl moiety (R-3) at the para-position of the P1' benzyl fragment generated compounds with antiviral potency in the low single digit nanomolar range. Halogenation or alkylation of the metabolic hot spots on the various aromatic rings resulted in PIs with high stability against degradation in human liver microsomes and low plasma clearance in rats. Replacing the chromanolamine moiety (R-1) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16-22) with EC(50)s on wildtype HIV-1 in the range of 0.8-1.8 nM. PIs 18 and 22, formulated as nanosuspensions, showed gradual but sustained and complete release from the injection site over two months in rats, and were therefore identified as interesting candidates for a LA injectable drug application for treating HIV/AIDS. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：310 / 317

页数：8

共 50 条

[1] Long-acting injectable antiretroviral for HIV-1 infection in adults
Halani, Sheliza
Tan, Darrell
Andany, Nisha
[J]. CANADIAN MEDICAL ASSOCIATION JOURNAL, 2024, 196 (25) : E888 - E889
[2] Long-acting injectable antiretroviral therapy for HIV-1 infection in adults
Halani, Sheliza
Tan, Darrell
Andany, Nisha
[J]. CANADIAN MEDICAL ASSOCIATION JOURNAL, 2024, 196 (10) : E341 - E342
[3] Development of potent and long-acting HIV-1 fusion inhibitors
Chong, Huihui
Wu, Xiyuan
Su, Yang
He, Yuxian
[J]. AIDS, 2016, 30 (08) : 1187 - 1196
[4] Computational drug design of new HIV-1 protease inhibitors
Lebon, F
Vinals, C
Feytmans, E
Durant, F
[J]. ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY, 1996, 104 (03) : B44 - B44
[5] Cabotegravir long-acting for HIV-1 prevention
Andrews, Chasity D.
Heneine, Walid
[J]. CURRENT OPINION IN HIV AND AIDS, 2015, 10 (04) : 258 - 263
[6] THE DESIGN AND SYNTHESIS OF ORALLY BIOAVAILABLE HIV-1 PROTEASE INHIBITORS
HUFF, JR
VACCA, JP
DORSEY, BD
THOMPSON, WJ
GHOSH, AK
HUNGATE, RW
LEE, HY
DARKE, PL
EMINI, EA
SCHLEIF, WA
LIN, JH
CHEN, IW
HOLLOWAY, MK
ANDERSON, PS
[J]. JOURNAL OF CELLULAR BIOCHEMISTRY, 1994, : 130 - 130
[7] Design and synthesis of a novel series of HIV-1 protease inhibitors
Takashiro, E
Nakamura, Y
Miyamoto, S
Ozawa, Y
Sugiyama, A
Fujimoto, K
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 1999, 7 (09) : 2105 - 2114
[8] Design and synthesis of sulfoximine based inhibitors for HIV-1 protease
Raza, Abbas
Sham, Yuk Yin
Vince, Robert
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (20) : 5406 - 5410
[9] Long-Acting Injectable Drugs for HIV-1 Pre-Exposure Prophylaxis: Considerations for Africa
Moyo, Enos
Murewanhema, Grant
Musuka, Godfrey
Dzinamarira, Tafadzwa
[J]. TROPICAL MEDICINE AND INFECTIOUS DISEASE, 2022, 7 (08)
[10] THE APPLICATION OF COMPUTER-ASSISTED DRUG DESIGN IN THE DISCOVERY OF NONPEPTIDE HIV-1 PROTEASE INHIBITORS
LUNNEY, EA
HUMBLET, C
HAGEN, SE
TAIT, B
WILSON, M
DOMAGALA, JM
HUPE, L
FERGUSON, D
TUMMINO, PJ
HUPE, D
BHAT, TN
ERICKSON, JW
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1994, 207 : 45 - COMP

← 1 2 3 4 5 →