Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent

Cumming, Graham R.; Zhang, Tao; Scalabrino, Gaia; Frankish, Neil; Sheridan, Helen

doi:10.1021/acs.oprd.7b00258

Cited by 6 publications

(6 citation statements)

References 15 publications

(36 reference statements)

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“…152 Sclafani et al reported asymmetric pilot scale synthesis of a quaternary stereocenter-containing Nav 1.7 and Nav 1.8 voltage-gated sodium channel blocker funapide (130, TV-45070). 153 Cumming et al reported multikilogram scale stereoselective synthesis of a novel anti-inflammatory agent (131, PH46A), 154 which has completed phase 1 clinical trial (BioMed Central ISRCTN Registry, 2014). Dillon et al developed a kilogram-scale synthesis of tetrasubstituted carbon-containing muscarinic antagonist 132 (PF-3635659) to support clinical studies.…”

Section: Carbon-containing Molecules That Entered Developmentmentioning

confidence: 99%

Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon

2020

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A quaternary carbon bears four other carbon substituents or combination of four non-hydrogen substituents at four vertices of a tetrahedron. The spirocyclic quaternary carbon positioned at the center of a bioactive molecule offers conformational rigidity, which in turn reduces the penalty for conformational entropy. The quaternary carbon is a predominant feature of natural product structures and has been associated with more effective and selective binding to target proteins compared to planar compounds with a high sp 2 count. The presence of a quaternary carbon stereocenter allows the exploration of novel chemical space to obtain new molecules with enhanced three-dimensionality. These characteristics, coupled to an increasing awareness to develop sp 3 -rich molecules, boosted utility of quaternary carbon stereocenters in bioactive compounds. It is hoped that this Perspective will inspire the chemist to utilize quaternary carbon stereocenters to enhance potency, selectivity, and other drug-like properties.

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Section: Carbon-containing Molecules That Entered Developmentmentioning

confidence: 99%

Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon

2020

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“…In the original control reaction with ketone 3 alone under achiral phase transfer conditions, much of the starting material remained following overnight reaction, while the achiral PTC alkylation of ketone 3 was rapid [ 10 ]. This demonstrated that the conversion from ketone 3 to unsaturated ketone 9 under the reaction conditions was not facile, or that the elimination was readily reversible.…”

Section: Resultsmentioning

confidence: 99%

“… The current synthetic scheme of manufacturing PH46A [ 7 , 10 ]. Reagnets and Conditions : (I) trimethylsilyl trifluoromethanesulfonate, TEA, DCM, −70 °C to −75 °C, 3 h; (II) methyl 4-(bromomethyl)benzoate, potassium t -butoxide, MtBE, t -BuOH, room temperature, 3 h; (III) triisobutylaluminium (1.1 M) solution in toluene, toluene, −12 °C to 10 °C, 2 h; (IV) 30% NaOH, MeOH, reflux, 24 h; (V) chiral separation by simulated moving bed technology; (VI) N -methyl- d -glucamine, EtOH, water, 55 °C, 5 h. …”

Section: Figure Schemes and Tablesmentioning

confidence: 99%

“…The overall yield of the original synthetic method was considered to be less satisfactory due to the generation of an undesirable diastereoisomer hydroxyl ester racemic ( rac )- 6 at ~48% yield and the unwanted enantiomer ( R , R )- 7 at almost 50% isolation yield from its racemic mixture ( rac )- 7 [ 7 ]. The ketone reduction step (Step III) was subsequently optimised by the use of triisobutylaluminum (TiBA) affording the desired product, diastereoisomer ( rac )- 6 , in a good diastereoselectivity percentage (93%) [ 10 ]. Such a highly selective method has successfully been employed on multi-kilo scale in a GMP environment.…”

Section: Introductionmentioning

confidence: 99%

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Bioactive Indanes: Proof of Concept Study for Enantioselective Synthetic Routes to PH46A, a New Potential Anti-Inflammatory Agent

Zhang¹,

Scalabrino²,

Frankish

et al. 2018

Molecules

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PH46A is a single enantiomer and a member of the 1,2-indane dimer family. It has two contiguous stereogenic centers with S,S configurations, one of which being a quaternary center, which has been developed as a clinical candidate for the treatment of inflammatory and autoimmune conditions. The current synthetic route to PH46A involves the generation of an unwanted enantiomer (R,R)-7, thus reducing the final yield significantly. Therefore, we have investigated potential alternatives to improve the efficiency of this synthesis. The first phase of the study has demonstrated proof of principle for a chiral alkylation of ketone 3 using phase-transfer catalysis, providing a key intermediate ketone (S)-4. The parent alkaloids required for the synthesis of PH46A, quinine or cinchonidine, have also been identified. Promising enantiomeric excesses of up to 50% have been achieved to date, and the use of an alternative substrate, unsaturated ketone 9, has also opened up further avenues for optimisation in future studies. The second part of the study involved preliminary screening the effects of a panel of hydrolase enzymes on (rac)-4 in order to identify a potential chemo-enzymatic route to optimise the introduction of chirality into PH46A at early stage of the synthesis. The hydrolase module has also yielded positive results; enzyme AH-46 with MtBE providing a selectivity factor of 8.4 with enantiomeric excess of 77%. Overall, positive results were obtained in this proof of concept study described herein. It is believed that conditions of both chiral PTC alkylation and biocatalytic hydrolysis could be optimised to further enhance the selectivity and improve the overall yield. This work is currently ongoing.

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“…In continuation of our work, we more recently designed and synthesized a series of dimeric indane compounds, with two contiguous stereogenic centres, one of which is a quaternary centre. Some of these compounds possess potent anti-inflammatory activity, in particular, a lead chiral molecule PH46A with S,S configurations [14][15][16][17][18], has been identified by our group and was subject to a range of preclinical studies prior to entering a Phase I clinical trial [19]. ADME (Absorption, distribution, metabolism, and excretion) is one of the major elements involved in the drug discovery and development process.…”

Section: Introductionmentioning

confidence: 99%

Bioactive Indanes: Comparative in vitro Metabolism Study of PH46A, a New Potential Anti-inflammatory Agent and Biosynthesis of its Primary Metabolite PH132

Zhang¹,

Scalabrino²,

Frankish³

et al. 2018

J Drug Metab Toxicol

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PH46A is the lead of a new class of bioactive indanes with potential for the treatment of inflammatory bowel disease. A qualitative in vitro metabolism profile of PH46A was investigated in preclinical studies, and the rate of its metabolism in cryopreserved hepatocytes prepared from male Sprague Dawley rat, Beagle dog, Cynomolgus monkey and pooled mixed gender human was compared by LC-MS. The clearance order of PH46A was determined to be rat>dog>monkey>human. The species tested which exhibited the closest clearance values to the human was monkey. Following incubation of PH46A with cryopreserved hepatocytes, 5 metabolites were identified, including M1 (keto-PH46), M2 (PH46-OH, PH132), M3 (PH46-diOH), M4 (keto-glucuronide-PH46) and M5 (glucuronide conjugate-PH46). It was found that the human metabolites M2 and M5 were also present in rat, dog and monkey, while M1 was present in all species except monkey. M2 was detected in dog and monkey by LC1 conditions, but only in dog by LC2. Therefore, the metabolism in rat was most similar to human, in terms of the metabolites observed, but all putative human metabolites were present in rat and dog. We further explored the characterization of key metabolite M2 (PH46-OH). Identical PH46-OH was obtained via a bio-catalytic oxidation method from PH46 using rat liver microsomes (RLM) and the human liver P450s (Cyp2D6, Cyp 2C19 and Cyp 4A11) following screening of selectAZyme panels of microbial P450s, recombinant human liver P450s and different microsomes. RLM was used in scale up production and PH132 was isolated and characterized as 4-(((1'S,2'S)-1',6-dihydroxy-1',3'-dihydro-1H,2'H-[2,2'-biinden]-2'-yl)methyl) benzoic acid via LC-MS/MS, NMR and HRMS. The site of hydroxylation on the biindane scaffold was unexpected. The outcomes of these studies have provided valuable information for future pharmacokinetic and in vivo toxicological investigations.

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Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent

Cited by 6 publications

References 15 publications

Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon

Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon

Bioactive Indanes: Proof of Concept Study for Enantioselective Synthetic Routes to PH46A, a New Potential Anti-Inflammatory Agent

Bioactive Indanes: Comparative in vitro Metabolism Study of PH46A, a New Potential Anti-inflammatory Agent and Biosynthesis of its Primary Metabolite PH132

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