Discovery and Preclinical Profiling of GSK3839919, a Potent HIV-1 Allosteric Integrase Inhibitor

Abstract

Allosteric HIV-1 integrase inhibitors (ALLINIs) have been of interest recently because of their novel mechanism of action. Strategic modifications to the C5 moiety of a class of 4-(4,4dimethylpiperidinyl)-2,6-dimethylpyridinyl ALLINIs led to the identification of a tetrahydroisoquinoline heterocycle as a suitable spacer element to project the distal hydrophobic aryl ring. Subsequent optimization of the aryl substitutions identified 12 as an ALLINI with single-digit nanomolar inhibitory potency and low clearance across preclinical species. In preclinical toxicology studies with 12 in rats, lipid hepatocellular vacuolation was observed. Removal of the C6 methyl group resulted in GSK3839919 ( 22), which exhibited a reduced incidence and severity of lipid vacuolation in both in vitro assays and in vivo studies while maintaining the potency and pharmacokinetic (PK) properties of the prototype. The virology, PK, and toxicology profiles of 22 are discussed.

Expeditious Synthesis of a Potent Allosteric HIV-1 Integrase Inhibitor GSK3839919A

“…The primary alcohol of 16 was oxidized to generate aldehyde 18, which was further oxidized to carboxylic acid improved via crystallization of the diastereomeric salts with (1S)-(+)-10-camphorsulfonic acid, followed by the salt break to provide 4 in >99% ee. 7,8 The long linear synthesis of 4 was viewed as a major impediment for further exploration of structure−activity relationships (SARs) in the ALLINI discovery program as well as the development of 1 as a drug candidate. Therefore, a more expeditious synthesis of 4 was required to support this work.…”

“…6 The (S)-pyridin-3-yl-2-(t-butoxy)acetic acid, represented by structure A in Figure 1, is an important pharmacophore present in some of the potent ALLINIs including the development candidate GSK3839919A (1, Figure 1). 6,7 For the syntheses of molecules represented by A with R 3 being an aryl substituent, a Suzuki coupling between an aryl boronic ester and 3-bromopyridine is frequently utilized as shown in Scheme 1 with GSK3839919A (1) as an example. 6,7 This approach, usually the most convergent, takes advantage of the good tolerability of other functional groups under typical Suzuki conditions.…”

“…The ( S )-pyridin-3-yl-2-( t -butoxy)­acetic acid, represented by structure A in Figure , is an important pharmacophore present in some of the potent ALLINIs including the development candidate GSK3839919A ( 1 , Figure ). , …”

“…For the syntheses of molecules represented by A with R 3 being an aryl substituent, a Suzuki coupling between an aryl boronic ester and 3-bromopyridine is frequently utilized as shown in Scheme with GSK3839919A ( 1 ) as an example. , This approach, usually the most convergent, takes advantage of the good tolerability of other functional groups under typical Suzuki conditions. The overall efficiency of the synthesis depends on the synthesis of components 3 and 4 .…”

“…For GSK3839919A ( 1 ), the original synthesis of 4 from the commercially available 2,6-dimethylpyridin-4-ol ( 5 ) required 13 steps as shown in Scheme . ,, This was a major issue when expeditious production of multi-kilogram quantities of 1 was required to support the drug development of the highly potent ALLINI inhibitor.…”