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Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors.

Abstract：

:The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Li G,Meanwell NA,Krystal MR,Langley DR,Naidu BN,Sivaprakasam P,Lewis H,Kish K,Khan JA,Ng A,Trainor GL,Cianci C,Dicker IB,Walker MA,Lin Z,Protack T,Discotto L,Jenkins S,Gerritz SW,Pendri A

doi

10.1021/acs.jmedchem.9b01681

subject

Has Abstract

pub_date

2020-03-12 00:00:00

pages

2620-2637

issue

5

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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