HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug-drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of 1 but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of 1 when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with 1, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs.
PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an L-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative L-Phe-Sar dipeptide derivative 74 that gave fourfold improved AUC and eight-fold higher C trough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.
Indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as a target for small-molecule immunotherapy for the treatment of a variety of cancers including renal cell carcinoma and metastatic melanoma. This work focuses on the identification of IDO1 inhibitors containing replacements or isosteres for the amide found in BMS-986205, an amide-containing, IDO1-selective inhibitor currently in phase III clinical trials. Detailed subsequently are efforts to identify a structurally differentiated IDO1 inhibitor via the pursuit of a variety of heterocyclic isosteres, leading to the discovery of highly potent, imidazopyridine-containing IDO1 inhibitors.
Structure–property relationships associated with
a series
of (carbonyl)oxyalkyl amino acid ester prodrugs of the marketed HIV-1
protease inhibitor atazanavir (1), designed to enhance
the systemic drug delivery, were examined. Compared to previously
reported prodrugs, optimized candidates delivered significantly enhanced
plasma exposure and trough concentration (C
min at 24 h) of 1 in rats while revealing differentiated
PK paradigms based on the kinetics of prodrug activation and drug
release. Prodrugs incorporating primary amine-containing amino acid
promoieties offered the benefit of rapid bioactivation that translated
into low circulating levels of the prodrug while delivering a high C
max value of 1. Interestingly,
the kinetic profile of prodrug cleavage could be tailored for slower
activation by structural modification of the amino terminus to either
a tertiary amine or a dipeptide motif, which conferred a circulating
depot of the prodrug that orchestrated a sustained release of 1 along with substantially reduced C
max and a further enhanced C
min.
IDO1
inhibitors have shown promise as immunotherapies for the treatment
of a variety of cancers, including metastatic melanoma and renal cell
carcinoma. We recently reported the identification of several novel
heme-displacing IDO1 inhibitors, including the clinical molecules
linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines
that, while being present in successful medicines, are known to be
potentially susceptible to oxidative metabolism. Efforts to swap this
quinoline with an alternative aromatic system led to the discovery
of 2,3-disubstituted pyridines as suitable replacements. Further optimization,
which included lowering ClogP in combination with strategic fluorine
incorporation, led to the discovery of compound 29, a
potent, selective IDO1 inhibitor with robust pharmacodynamic activity
in a mouse xenograft model.
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