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Letter
Long-lasting and fast-acting in vivo efficacious antiplasmodial azepanylcarbazole amino alcohol Nada Abla, Sridevi Bashyam, Susan A. Charman, Béatrice Greco, Philip Hewitt, Maria Belén Jiménez-Díaz, Kasiram Katneni, Holger Kubas, Didier Picard, Yuvaraj Sambandan, Laura X Sanz, Dennis A. Smith, Tai Wang, Paul A. Willis, Sergio Wittlin, and Thomas Spangenberg ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00391 • Publication Date (Web): 28 Nov 2017 Downloaded from http://pubs.acs.org on December 4, 2017
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ACS Medicinal Chemistry Letters
Long-lasting and fast-acting in vivo efficacious antiplasmodial azepanylcarbazole amino alcohol. Nada Abla,1,3 Sridevi Bashyam,4 Susan A. Charman,8 Béatrice Greco,1 Philip Hewitt,2 Maria Belén Jiménez-Díaz,6† Kasiram Katneni,8 Holger Kubas,2 Didier Picard,9 Yuvaraj Sambandan,4 Laura Sanz,6 Dennis Smith,7 Tai Wang,9†† Paul Willis,3 Sergio Wittlin,5 Thomas Spangenberg1* 1
Merck Global Health Institute, Ares Trading S.A., a subsidiary of Merck KGaA (Darmstadt, Germany), Coinsins, Switzerland, 2Merck, KGaA, Darmstadt, Germany, 3Medicines for Malaria Venture, Geneva, Switzerland, 4Syngene International, Bangalore, India, 5Swiss TPH, Basel, Switzerland, 6GSK,Tres Cantos, Spain, 7MMV Expert Scientific Advisory Committee; 8 Centre for Drug Candidate Optimisation, Monash University, Parkville, VIC, Australia ; 9Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, CH-1211, Genève 4, Switzerland. KEYWORDS antiplasmodial • carbazole • amino alcohol • pharmacokinetics • pharmacodynamics • Hsp90 ABSTRACT: With ~429,000 deaths in 2016, malaria remains a major infectious disease where the need to treat the fever symptoms, but also to provide relevant post-treatment prophylaxis, is of major importance. An azepanylcarbazole amino alcohol is disclosed with a long- and fast-acting in vivo antiplasmodial efficacy and which meets numerous attributes of a desired post-treatment chemoprophylactic antimalarial agent. The synthesis, the parasitological characterization, the animal pharmacokinetics and pharmacodynamics of this compound are presented along with a proposed target.
One third of the world’s population is at risk of malaria, a disease caused by protozoan parasites of the genus Plasmodium upon an infectious mosquito bite. Although the burden of malaria has reduced by 37% since 2000, the number of victims remains unacceptable with ~429,000 deaths in 2016 where a vast majority are children below 5 years of age.1 Cases of malaria are seasonal due to the seasonal difference in the abundance of the mosquito vector and subjects can undergo multiple malaria infections/re-infections in a year, therefore highlighting the need to treat the acute infection and also to provide relevant post-treatment prophylaxis. This target compound profile has been framed as being a long-acting blood stage antimalarial.2 Ideally, this compound should be able to maintain its efficacious plasma concentration for at least four weeks, which is typically needed in high transmission areas with high reinfection rates, thus providing significant posttreatment prophylaxis.2 Identifying molecules which have a very long half-life is challenging as they are typically highly lipophilic and are often bases, both of which increase the affinity for tissue membranes and thereby increase the volume of distribution and resulting half-life. Consequently, such molecules have a higher risk to be promiscuous for human receptors and cause adverse events.3,4 Examples of long acting blood stage antimalarial agents are piperaquine (4aminoquinoline) and mefloquine (amino alcohol) with halflives of 33 and 14 to 28 days, respectively.5,6 Based on previous work on antiplasmodial acyclic and racemic amino-alcohol carbazoles,7 we disclose the synthesis, the parasitological characterization, the animal pharmacokinetics and pharmacodynamics of compound (-)-1, a member of a novel azepanyl amino alcohol carbazole series (Figure 1). The latter has shown improvement of the acyclic series as it met
numerous attributes of a desired fast and long acting antimalarial agent. Also as opposed to its enantiomer, (-)-1 showed reduced binding on monoamine transporters (i.e. norepinephrine, dopamine and 5-HT, see Supporting Information). Carbazole scaffolds are found in nature, with reported antiplasmodial activity.8.9.10 Also synthetic analogues have been described with such activity along with BAX channel modulation and more recently as neuroprotective agents.11,12,13,14 Compound (-)-1 [(3S,4S)-4-(3,6-bis(trifluoromethyl)-9Hcarbazol-9-yl)azepan-3-ol] is a representative member of the series and has an 3S,4S absolute stereochemistry configuration. Figure 1 depicts the chemical route for the rapid access to optically active (-)-1 in 5 linear steps and one chiral resolution on a multi-gram scale. The 3,6-bis(trifluoromethyl)-9H-carbazole, 6, was obtained efficiently in two steps using palladium-mediated couplings. First, p-(trifluoromethyl)aniline was assembled with p(trifluoromethyl)iodobenzene through a Buchwald-Hartwig cross-coupling reaction to produce the desired adduct, 7, in 96% yield. Then an intramolecular palladium(II)-catalyzed coupling via C−H activation of the diarylamine, 7, yielded the desired carbazole, 6, in 56%.15 In parallel, the use of standard alkylating procedures enabled the formation of the bis-olefin, 5, with a yield of 87%. Next, a 5% loading of Grubbs I catalyst afforded the cyclic olefin, 4, by ring closing metathesis in 57% yield. The latter product was reacted with m-CPBA to form the desired epoxide, 3, with a yield of 44%. Finally, the carbazole, 6, and the epoxide, 3, were treated with cesium carbonate in DMF to allow – with a favorable regioselectivity of 2:1 – the slow formation of the desired trans-isomer, 2, resulting in an isolated yield of 39%. At that stage no residue (99.9%), resulting in low calculated free brain concentrations and expected high safety margins vs. brain targets. MW (g/mol) LogP / LogD pH 7.4* pKa* Solubility in µg/mL Microsomal CLint in µL/min/mg prot Caco-2 Permeability (Papp x 10-6 cm/s) Plasma Protein binding: Fub in % Blood/Plasma ratio
416.36 4.6 / 4.1 8.05 1.5 (PBS., pH 7.4); 10 (FaSSIF pH 6.5); 83.5 (FeSSIF pH 5) Human
