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.

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

“…Li et al reported an approach using large quantities of the starting materials 47a and 18 obtaining a dihydro derivative (not shown). Subsequently, the authors achieved an oxidation with DDQ without an intermediate purification step involved, to produce the unsaturated product 49 in 64% yield ( Scheme 16 a) [ 55 ].…”

“…The reaction results are widely employed in medicinal chemistry because it allows modifications with various structural motifs at electrophilic positions of the pyrimidine ring. Recently, it has been employed with the aim of adding aromatic amines [ 34 , 67 ], alkylamines [ 48 , 76 ], cycloalkylamines [ 55 , 77 , 78 ], and substituted alkoxides [ 67 ]. In this respect, McNally, Paton, and co-workers designed an interesting way of coupling the 5-(diphenylphosphanyl)pyridine 118 to the position 7 of the fused pyrazole PP , generating the phosphonium salt 119 according to the authors [ 79 ].…”

“…Similarly, Li and co-workers reported a protocol to obtain formyl group at position 6 of 139 employing an ester moiety. The authors performed a reduction of 139 with a selective hydride donor (DIBAL-H) [ 55 ]. However, due to excess reductive reagent, the alcohol 141 was mainly obtained, which after purification suffered an oxidation reaction with PCC, obtaining the desired aldehyde 140 in a good yield ( Scheme 40 b) [ 55 ].…”

“…The authors performed a reduction of 139 with a selective hydride donor (DIBAL-H) [ 55 ]. However, due to excess reductive reagent, the alcohol 141 was mainly obtained, which after purification suffered an oxidation reaction with PCC, obtaining the desired aldehyde 140 in a good yield ( Scheme 40 b) [ 55 ]. The authors report the reaction performance at room temperature for both protocols; the ester moiety could be less electrophilic than expected because of its electronic participation in the heteroaryl.…”

Structure of a HIV-1 IN-Allosteric Inhibitor Complex at 2.93 Å Resolution: Routes to Inhibitor Optimization

“…Another class of integrase inhibitors, the allosteric inhibitors (ALLINIs) (Figure 1B) target the pocket normally occupied by the integrase-binding domain (IBD) of the lens epithelium-derived growth factor (LEDGF/p75)(36-39) (Figure 1C). LEDGF binds to IN and directs the IN-cDNA complex toward transcriptionally active areas of the genome for integration(40-42).…”