Long-acting
(LA) human immunodeficiency virus-1 (HIV-1) antiretroviral
therapy characterized by a ≥1 month dosing interval offers
significant advantages over daily oral therapy. However, the criteria
for compounds that enter clinical development are high. Exceptional
potency and low plasma clearance are required to meet dose size requirements;
excellent chemical stability and/or crystalline form stability is
required to meet formulation requirements, and new antivirals in HIV-1
therapy need to be largely free of side effects and drug–drug
interactions. In view of these challenges, the discovery that capsid
inhibitors comprising a quinazolinone core tolerate a wide range of
structural modifications while maintaining picomolar potency against
HIV-1 infection in vitro, are assembled efficiently
in a multi-component reaction, and can be isolated in a stereochemically
pure form is reported herein. The detailed characterization of a prototypical
compound, GSK878, is presented, including an X-ray co-crystal structure
and subcutaneous and intramuscular pharmacokinetic data in rats and
dogs.
The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1−P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1−P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF 3 Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1′ cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD 3 O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD 3 O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH 3 O prototype.
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.
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