The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability. Medicinal chemistry efforts have resulted in more than 10 clinical candidates, although clinical candidates have failed to demonstrate superior efficacy compared to placebo or existing antidepressants. Hence, the successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability. TRIs also hold therapeutic potential for other indications, with four candidates under clinical development for attention deficit hyperactivity disorder, binge eating disorder, cocaine addiction, obesity, and type 2 diabetes. Clinical studies have indicated a lower abuse potential for TRIs than psychostimulants.

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.

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.

Organoborane reagents were investigated as coupling partners to cyclopropanol-derived β-ketone enolates in the presence of a chelated Pd(II) catalyst. Efficient coupling of a range of electronically and sterically diverse cyclopropanols and aryl/ alkenyl boronic derivatives (39 examples, 65−94% yield) could be achieved with the generation of synthetically important β-aryl ketone intermediates in a chemoselective fashion. This reactivity paradigm, which broadens the scope of aryl donor partners to homoenolates, allows open-flask conditions, water as a cosolvent, and preparation of halogen-bearing β-aryl ketones that are distinct from previous methods. This chelated Pd(II) catalysis appears to be different from the Pd(0) pathway, as evident from deuterium scrambling studies that could reveal differentiating protonolysis of an α-keto carbopalladium complex in the terminal step.

The scope of an umpolung approach to expand synthetic access to bifunctional γ-keto hydrazine intermediates via electrophilic amination of β-homoenolates derived from cyclopropanol precursors that took advantage of azodicarboxylates or azodicarboxamides as electron-deficient nitrogen sources was examined. This new synthetic procedure avails commercially available or readily accessible starting materials along with a ligand-free Cu(II) salt as an inexpensive catalyst. Using this operationally simple reaction, which proceeds under mild conditions (open-flask and ambient temperature) and is suitable for multigram scale, preparative applications were established with a range of aryl-and alkyl-substituted cyclopropanols and azodicarboxylate/ azodicarboxamide substrates (26 examples, 74−95% yields). Further, the obtained products have been shown to provide convenient synthetic access to γ-hydroxy hydrazide, γ-amino hydrazide, and heterocyclic derivatives.

The scope of chemoselective β-hydride elimination in the context of arylation/alkenylation of homoenolates from cyclopropanol precursors using organoboronic reagents as transmetalation coupling partners was examined. The reaction optimization paradigm revealed a simple ligand-free Pd(II) catalytic system to be most efficient under open air conditions. The preparative scope, which was investigated with 48 examples, supported the applicability of this reaction to a wide range of substrates tolerating a variety of functional groups while delivering β-substituted enone and dienone derivatives in 62−95% yields.