Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors

Abstract

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.

Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition

“…29 The pyridone-aminal chemotype has not been reported in kinase inhibitors to date. 30,31 Compound 23 activity in models of diffuse large cell B-cell lymphoma (DLBCL) is associated with potent p-eIF4E knockdown and selective destabilization of pro-inflammatory cytokine mRNA. Pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), and TNFα, are drivers of many hallmarks of cancer, e.g., tumor cell survival, migration and invasion, angiogenesis, immune evasion, and stress response, while affecting drug resistance.…”

“…We have designed a highly selective and potent MNK1/2 inhibitor, compound 23 (eFT508), leveraging the unique active site of this kinase in an iterative structure-based approach . The pyridone-aminal chemotype has not been reported in kinase inhibitors to date. , Compound 23 activity in models of diffuse large cell B-cell lymphoma (DLBCL) is associated with potent p-eIF4E knockdown and selective destabilization of pro-inflammatory cytokine mRNA. Pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), and TNFα, are drivers of many hallmarks of cancer, e.g., tumor cell survival, migration and invasion, angiogenesis, immune evasion, and stress response, while affecting drug resistance. , Importantly, this p-eIF4E and cytokine knockdown translates into potent in vivo antitumor activity in DLBCL models harboring activating MyD88 mutations, consistent with the MNKs being activated by TLR signaling. , In addition, efficacy has been demonstrated in solid tumor settings, which may reflect the MNKs’ impact on mRNA translation that controls tumor and stromal cell signaling.…”

Asymmetric Synthesis of a Potent HIV-1 Integrase Inhibitor

“…Having established that the general route to intermediate 15 employing the chemistry utilized for the manufacture of compound 4 (Scheme ) was unsuitable for scale up due to low yields and the need for chromatography, our attention turned to identifying an alternative route. It was envisioned that reordering of the sequence of steps and removal of the sulfur byproducts formed in the thermal elimination step by crystallization would offer significant advantages in terms of controlling the product purity and yields . To this end, compound 11 was prepared as described in Scheme .…”

Close‐up: HIV/SIV intasome structures shed new light on integrase inhibitor binding and viral escape mechanisms

“…Second-generation compounds dolutegravir (DTG) and bictegravir (BIC) impart comparatively high barriers to the development of drug resistance [8,9] and are accordingly preferred components of current frontline and drug-switch ART formulations [10]. Other advanced compounds, not yet approved for clinical applications, similar to DTG and BIC display drug resistance profiles that are superior to the first-generation compounds [11][12][13][14][15][16].…”