Aliphatic Rings as Bioisosteres of Phenyl Ring(Issue 6)

Aliphatic Rings as Bioisosteres of Phenyl Ring(Issue 6)

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By Jin Li

The high prevalence of benzene rings in marketed drugs reflects its fundamental importance as both a structural and pharmacophoric element in drug design. Meanwhile, its versatility qualifies it as the preeminent privileged scaffold. [1] However, there are several issues associated with phenyl ring, including low aqueous solubility, poor metabolic stability, membrane permeability, etc. To circumvent these drawbacks, significant effort has been dedicated to exploring the design of bioisosteric replacements for phenyl rings that would offer advantageous properties. [2] Among them, sp3-riched aliphatic rings, including monocyclic and bicyclic, have emerged as frequently used bioisosteres of the phenyl ring (Figure 1).

Figure 1. Sp3-riched aliphatic rings as bioisosteres of the phenyl ring to circumvent critical issues.


Compound 63 (AMG-517) is Amgen’s first-generation TRPV1 antagonist which was evaluated in clinical trials. However, it was found to have low aqueous solubility (< 1 ug/mL). The goal to identify a novel second-generation clinical candidate with increased aqueous solubility was achieved by replacing the phenyl ring with sp3-riched aliphatic rings (Figure 2). [3] Cyclohexene in compound 64, cyclohexane in compound 65 and piperidine in compound 66 were used as bioisosteres of the phenyl ring in compound 63, and all of them increased aqueous solubility significantly. In studies of the structure-solubility relationship, diverse cyclohexenyl boronic acid pinacol ester building blocks played crucial roles in quick synthesis of designed molecules.

Figure 2. Cyclohexene, cyclohexane and piperidine increased aqueous solubility.


In the course of discovering a novel selective PDE9A inhibitor, compound 67 was identified as an early lead compound with excellent PDE9A inhibition and good selectivities against PDE family members (Figure 3). [4] However, in studies of the PK profile of compound 67 in rats, high clearance and low bioavailability were observed, which was attributed to extensive phase 2 metabolism. Replacement of the 4-methylphenyl group in compound 67 with 4-dimethylpiperidine afforded compound 68, which interestingly showed no phase 2 glucuronidation metabolism after incubation in rat hepatocytes. Although without phase 2 metabolism, the oral bioavailability of compound 68 was slightly improved. It was found that the main clearance pathway of compound 68 was driven by oxidative metabolism. It was hypothesized that cyclopropane can be metabolically more stable than the corresponding gem-dimethyl analogue. With this hypothesis in mind, compound 69 which has a spiro-piperidine motif was identified. It was fascinating that compound 69 (BAY-7081) improved bioavailability significantly. In the discovery campaign, diverse spiro-piperidine building blocks played crucial roles in quickly synthesizing designed molecules.

Figure 3. Piperidines as bioisosteres of the phenyl ring improved PK profiles.


Compound 70 was originally discovered as a novel potent SETD2 inhibitor (Figure 4). [5] The structure contains an aniline motif which impacts less-than-ideal pharmacokinetic properties and potential metabolism-derived toxicities. The team has experienced before that saturating of the phenyl ring significantly improved the physicochemical properties of the series and avoided the potential AMES toxicity. With this in mind, the replacement of the phenyl ring in compound 70 with cis-cyclohexane in compound 71 improved clearance and oral bioavailability significantly. There are two chiral centers on the 1,3-disubstituted cyclohexane ring, and chirally pure bifunctional cyclohexane building blocks played crucial roles in quick SAR and SPR studies.

Figure 4. Cyclohexanes as bioisosteres of the phenyl ring improved PK profile.


Although bicylco[1.1.1]pentane (BCP) has a different stereoelectronic property compared to the 1,4-disubstituted phenyl ring, it shares comparable dihedral angle and similar distance and coplanar linear disposition of the substituents (Figure 5). [1] BCP system significantly increase aqueous solubility and noticeably decreases nonspecific binding. Consequently, the sp3-riched BCP system serves as a nonclassical phenyl bioisostere to escape from flatland imposed by high aromatic ring count and modulate physicochemical properties during lead optimization. For instance, isosteric replacement of the 1,4-disubstituted phenyl ring with BCP has been shown to confer significant improved passive permeability and aqueous solubility. however, it should be noted that such bioisosteric replacement strategy will not be effective in lead compounds where a 1,4-disubstituted phenyl ring plays a pharmacophore role such as pi-pi stacking or pi-cation interactions with the aromatic or positively charged residue of the target protein. [6]

Figure 5. Geometrical parameters of phenyl ring and BCP ring


The significant advantage of the BCP moiety in compound 73 over the phenyl ring in compound 72 was manifested in physicochemical properties, with aqueous solubility increased by 360-fold and clearance decreased by at least 4-fold (Figure 6). It is noteworthy that this case story is one of the earliest examples using BCP as a bioisostere of the phenyl ring. [7]

Figure 6. Representative examples where BCP improved ADME and PK profiles over the phenyl ring


The natural product 74 is associated with a wide range of biological activities. However, the poor bioavailability in preclinical species and humans has hampered its clinical progression, which can be attributed, in part, to metabolic modification of the phenolic hydroxyl moieties which are subjected to rapid first-pass glucuronidation or sulfation. An interesting approach to improve the pharmacokinetic profile of compound 74 was conceived of replacing the phenol ring with a hydroxyl-substituted BCP moiety, explored in the context of compound 75 (Figure 6). [8] The BCP moiety dramatically increased aqueous solubility by 32-fold, and improved hepatocyte half-time by at least 3-fold which translated into 12-fold higher exposure.


The compound 76 exhibited a poor physicochemical profile, with an aqueous solubility of less than 1 ug/mL that was reflective of the overall planar nature of the structure (Figure 6). [9] The strategy adopted to address this deficiency was to replace the phenyl ring with a range of sp3-riched bioisosteres. Among of them, BCP in compound 77 increased aqueous solubility significantly by at least 880-fold.

Despite the presence of the piperazine heterocycle, a basic element introduced to support salt formation as a means of enhancing aqueous solubility, the solubility of compound 78 is low at 0.01 mg/mL (Figure 6). [10] It was anticipated that reducing the aryl ring count by introducing the sp3-riched, nonaromatic structural motifs would productively modulate physicochemical properties by lowering lipophilicity and enhancing aqueous solubility. This hypothesis was proved to be correct, with aqueous solubility increased by 87-fold in compound 79 in which BCP was used as bioisostere of the phenyl ring.


Compound 80 showed high membrane permeability and low aqueous solubility (BCS II). Based on assumption that reducing aromatic ring count and disrupting the planarity associated with the biaryl system would lead to improved physicochemical profiles, the effect of replacing the central phenyl ring with a BCP isostere was examined in the compound 81 (Figure 6). [11] Compound 81 has both improved aqueous solubility and membrane permeability (BCS I).


With the great success achieved in the application of BCP as bioisostere of the phenyl ring, efficient access to diverse BCP building blocks is of substantial need, including monofunctional BCP building blocks (amines, carboxylic acids, etc.) and difunctional BCP building blocks (Figure 7).

Figure 7. BCP building blocks have been widely used in medicinal chemistry.


Besides the bicyclo[1.1.1]pentane (BCP) ring system, the bicyclo[2.2.2]octane (BCO) ring system is another commonly used bioisostere of the phenyl ring by medicinal chemists. As part of a study of structurally novel HCV NS5A inhibitors, the replacement of the biphenyl scaffold of compound 82 with alternative conformationally constrained spacers offering improved physicochemical properties was explored in a survey that included BCO-phenyl motif in compound 83. The aqueous solubility was increased by 6-fold which was translated into high oral bioavailability (Figure 8). [12]

As described previously, compound 76 exhibited a poor physicochemical profile, with an aqueous solubility of less than 1 ug/mL that was reflective of the overall planar nature of the structure. The team also used BCO in compound 84 to replace the phenyl ring to improve aqueous solubility by at least 150-fold (Figure 8). [9]

Compound 85 caused only partial tumor regression in a mouse model attributed to low in vivo exposure. To address the PK deficiency, the benzoic acid was replaced with the conformationally rigid, sp3-riched BCO ring system in compound 86. Cmax and AUC were improved dramatically by 5-fold and 11-fold respectively (Figure 8). [13]

Figure 8. Representative examples where BCO improved ADME and PK profiles over the phenyl ring


Like BCP, great success was also achieved in application of BCO as bioisostere of the phenyl ring. Therefore, an efficient access of diverse BCO building blocks is of substantial need for medicinal chemists, including monofunctional BCO building blocks (amines, carboxylic acids) and difunctional BCO building blocks (Figure 9).

Figure 9. Like BCP, BCO building blocks have also been widely used in medicinal chemistry.


The altered geometries associated with the introduction of an oxygen atom into the skeleton of a BCP moiety confers plausible mimicry between 2-oxabicyclo[2.1.1]hexanes and meta-disubstituted benzene as depicted in Figure 10. [1]

Figure 10. Geometric parameters of the phenyl ring and oxabicyclo[2.1.1]hexane ring system


Replacement of the phenyl ring of compound 87 with a 2-oxabicyclo[2.1.1]hexane ring system resulted in at least 6-fold improvement in aqueous solubility in both compound 89 and 90 (Figure 11). [14] Besides, there is a potential IMHB between the ring oxygen atom and the amide N-H in compound 90, which would reduce both the exposed polarity and solvation.

Figure 11. 2-Oxabicyclo[2.1.1]hexane moiety increased aqueous solubility.


As described previously, compound 76 exhibited a poor physicochemical profile, with an aqueous solubility of less than 1 ug/mL that was reflective of the overall planar nature of the structure. The team also used bridged piperidine in compound 91 to replace the phenyl ring to improve aqueous solubility by at least 1040-fold (Figure 12). [9] Besides, compound 91 exhibited improved potency by almost 10-fold.

Figure 12. Bridged piperidine increased both aqueous solubility and potency.


References

[1] Murugaiah A. M. Subbaiah; et al. Bioisosteres of the phenyl ring: recent strategic applications in lead optimization and drug design. J. Med. Chem. 2021, 64, 14046-14128.

[2] Mykhailiuk P. K. Saturated bioisosteres of benzene: where to go next? Org. Biomol. Chem. 2019, 17, 2839-2849.

[3] Hui-ling Wang; et al. Novel vanilloid receptor-1 antagonists: 3. The identification of a second-generation clinical candidate with improved physicochemical and pharmacokinetic properties. J. Med. Chem. 2007, 50, 3528-3539.

[4] Daniel Meibom; et al. BAY-7081: a potent, selective, and orally bioavailable cyanopyridone-based PDE9A inhibitor. J. Med. Chem. 2022, 65, 16420-16431.

[5] Joshua S. Alford; et al. Conformational-design-driven discovery of EZM0414: a selective, potent SETD2 inhibitor for clinical studies. ACS Med. Chem. Lett. 2022, 13, 1137-1143.

[6] Tanaji T. Talele Opportunities for tapping into three-dimensional chemical space through a quaternary carbon. J. Med. Chem. 2020, 63, 13291-13315.

[7] Stepan A. F.; et al. Application of the bicycle[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active r-secretase inhibitor. J. Med. Chem. 2012, 55, 3414-3424.

[8] Goh Y. L.; et al. Toward resolving the resveratrol conundrum: synthesis and in vivo pharmacokinetic evaluation of BCP-resveratrol. ACS Med. Chem. Lett. 2017, 8, 516-520.

[9] Ratni H.; et al. Phenyl bioisosteres in medicinal chemistry: discovery of novel r-secretase modulators as a potential treatment for Alzheimer’s disease. RSC Med. Chem. 2012, 12, 758-766.

[10] Nicolaou K. C.; et al. Synthesis and biopharmaceutical evaluation of Imatinib analogues featuring unusual structural motifs. ChemMedChem 2016, 11, 31-37.

[11] Measom N. D.; et al. Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 inhibitor. ACS Med. Chem. Lett. 2017, 8, 43-48.

[12] Zhong M.; et al. Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 5731-5737.

[13] Aguilar A.; et al. Discovery of 4-((3’R,4’S,5’R)-6’-chloro-4’-(3-chloro-2-fluorophenyl)-1’-ethyl-2’-oxodispiro[cyclohexane-1,2’-pyrrolidine-3’,3’-indoline]-5’-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid (AA-115/APG-115): a potent and orally active murine double minute 2 (MDM2) inhibitor in clinical development. J. Med. Chem. 2017, 60, 2819-2839.

[14] Levterov V. V.; et al. Water-soluble non-classical benzene mimetics. Angew. Chem. Int. Ed. 2020, 59, 7161-7167.



About Author

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Jin Li

Senior Director of PharmaBlock


  • 10+ years’ experience in organic chemistry
  • 3+ years’ experience in medicinal chemistry
  • 10+ patents and papers published
  • Inventor of 2 clinical candidates
  • Email: [email protected] ????????


Find out more at www.pharmablock.com

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