Discovery of Benzimidazole CYP11B2 Inhibitors with <i>in Vivo</i> Activity in Rhesus Monkeys

Hoyt, Scott B.; Park, Min K.; London, Clare; Xiong, Yusheng; Tata, Jim; Bennett, David Jonathan; Cooke, Andrew; Cai, Jiaqiang; Carswell, Emma L.; Robinson, John; Maclean, John; Brown, Lindsay; Belshaw, Simone; Clarkson, Thomas R.; Liu, Kun; Liang, Gui-Bai; Struthers, Mary; Cully, Doris; Wisniewski, Tom; Ren, Ning; Bopp, Charlene; Sok, Andrea; Cai, Tian-Quan; Stribling, Sloan; Pai, Lee-Yuh; Ma, Xiaolong; Metzger, Joe; Verras, Andreas; McMasters, Daniel R.; Chen, Qing; Tung, Elaine C.; Tang, Wei; Salituro, Gino; Buist, Nicole; Kuethe, Jeff; Rivera, Nelo R.; Clemas, Joe; Zhou, Gaochao; Gibson, Jonathan; Maxwell, Carrie; Lassman, Mike; McLaughlin, Theresa; Castro-Perez, José; Szeto, Daphne; Forrest, Gail; Hajdu, Richard; Rosenbach, Mark; Ali, Amjad

doi:10.1021/acsmedchemlett.5b00054

Cited by 23 publications

(20 citation statements)

References 15 publications

(20 reference statements)

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“…Synthesis was strategically planned to make wide changes to each of the hydrophobic fragments of compound 1 : the benzimidazole ring, N -alkyl chain and amide as highlighted above. The aniline intermediate ii was prepared by aromatic nucleophilic substitution reaction (S N Ar)[ 21 ] of compound i (X = F or Cl) with primary N -alkylamines or with ammonia followed by reductive amination ( Fig 2 ). The syntheses of the final compounds ( 1–55 ) were performed from ii by reduction of the nitro group followed by cyclization using cyanogen bromide solution,[ 22 ] then coupling of the 2-aminobenzimidazoles iv with selected carboxylic acids ( Fig 2 ).…”

Section: Resultsmentioning

confidence: 99%

2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling

et al. 2021

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Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro properties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 μM) and 39 (L. infantum IC50: 0.5 μM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency.

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Section: Resultsmentioning

confidence: 99%

2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling

et al. 2021

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“…Given the favorable developability properties, the simple 2-(3-pyridyl) indole and benzimidazole screening hits 1 and 2 were selected for further evaluation (Figure 1). 12,16 Facile synthetic access to the benzimidazole scaffold allowed for efficient preparation of a series of inhibitors with varied MBGs (Table 1). 21 Following precedent, the benzimidazole core was adorned with N1 cyclopropyl and 6-fluoro substituents for the MBG scan with published data for pyridine-containing inhibitor 11 included for comparison.…”

mentioning

confidence: 99%

Development of Highly Selective Pyrimidine-Based Aldosterone Synthase (CYP11B2) Inhibitors

Sparks¹,

Danger²,

Hoekstra³

et al. 2019

ACS Med. Chem. Lett.

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Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme aldosterone synthase (CYP11B2) has been pursued to ameliorate the negative effects of elevated aldosterone. Herein, we report the development of aldosterone synthase inhibitors using a pyrimidine-based metal binding group leading to the highly selective CYP11B2 inhibitor 22. Superior selectivity combined with robust pharmacokinetics afforded highly selective in vivo aldosterone suppression in a monkey model of adrenal steroidogenesis, demonstrating the potential for selective aldosterone lowering in humans with pyrimidine 22.

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“…Radioactivity report on telmisartan 8 showed that >98% was excreted via the feces while urinary excretion accounted for <1% of the dose . Compound 233 showed improvements in plasma clearance, half‐life, and oral exposure in rat and half‐life of 7.4 h in rhesus while 234 exhibited maximal reductions in plasma aldosterone AUC and better elimination . Evaluation of metabolic stability and excretion study using mouse and human liver microsomes showed high stability for 235 (79% and 52% of it remaining after 1 h) .…”

Section: Pharmacokinetics/pharmacodynamics Of Benzimdazolementioning

confidence: 97%

Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine

Ajani

Aderohunmu

Ikpo

et al. 2016

Archiv der Pharmazie

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Benzimidazole derivatives are crucial structural scaffolds found in diverse libraries of biologically active compounds which are therapeutically useful agents in drug discovery and medicinal research. They are structural isosteres of naturally occurring nucleotides, which allows them to interact with the biopolymers of living systems. Hence, there is a need to couple the latest information with the earlier documentations to understand the current status of the benzimidazole nucleus in medicinal chemistry research. This present work unveils the benzimidazole core as a multifunctional nucleus that serves as a resourceful tool of information for synthetic modifications of old existing candidates in order to tackle drug resistance bottlenecks in therapeutic medicine. This manuscript deals with the recent advances in the synthesis of benzimidazole derivatives, the widespread biological activities as well as pharmacokinetic reports. These present them as a toolbox for fighting infectious diseases and also make them excellent candidates for future drug design.

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Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

Cited by 23 publications

References 15 publications

2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling

2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling

Development of Highly Selective Pyrimidine-Based Aldosterone Synthase (CYP11B2) Inhibitors

Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine

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