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Jul
25

Building a complete picture of hERG SAR

A single potassium ion channel can spell the death knell for a drug discovery program. It’s name is hERG and you can find out why its consumed a lot of my time over a decade here, here, here, here, here and here. Capturing hERG structure activity relationships is a thankless job and I wished I had tracked this continually for the past decade rather than occasionally. Below are just a few papers papers from the past few years and some important features identified. There are probably 3-4 times as many again to collate…Why you might ask? Well it seems that with all the models and medicinal chemistry insight researchers still run up against it in many programs. It is time we nailed this completely. We should be capturing what we need to avoid in a molecule and what we can  add or subtract from molecules to alleviate it – in an open forum..Its a dream and I am sure hERG has been an expensive nightmare for many, for far too long. I will be expanding this list as time permits.

Important features or descriptors identified

Reference

Basic nature of 4-aminopyridine

Liverton, N.J. et al. (2007) Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an orally bioavailable, brain penetrant NR2B selective N-methyl-D-aspartate receptor antagonist. J Med Chem 50 (4), 807-819

Tertiary amine and LogD

Ramnauth, J. et al. (2012) 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors: lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximi damide as a preclinical development candidate. J Med Chem 55 (6), 2882-2893

Added C=O, removed amide and added methyls

Kim, S.H. et al. (2011) III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl-piperazinyl-piperidine scaffold. Bioorg Med Chem Lett 21 (23), 6982-6986

Adding polar groups bearing hydrogen bond donors- rigid cyclobutoxy linker

Provins, L. et al. (2012) Lead optimization of thiazolo[5,4-c]piperidines: 3-cyclobutoxy linker as a key spacer for H(3)R inverse agonists. ChemMedChem 7 (12), 2087-2092

Carboxyl group reduced hERG activity

Ikuma, Y. et al. (2012) Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Bioorg Med Chem 20 (19), 5864-5883

ND

Barker, R.H., Jr. et al. (2011) Aminoindoles, a novel scaffold with potent activity against Plasmodium falciparum. Antimicrob Agents Chemother 55 (6), 2612-2622

Substitute fluorine for hydrogen on cyclopentyl ring reduces hERG activity

Sugimoto, Y. et al. (2009) Synthesis and biological evaluation of imidazole derivatives as novel NOP/ORL1 receptor antagonists: exploration and optimization of alternative pyrazole structure. Bioorg Med Chem Lett 19 (16), 4611-4616

Incorporated Nitrogen in aromatic ring reduces hERG activity

Suzuki, T. et al. (2009) Discovery of novel diarylketoxime derivatives as selective and orally active melanin-concentrating hormone 1 receptor antagonists. Bioorg Med Chem Lett 19 (18), 5339-5345

Incorporated Nitrogen in aromatic ring reduces hERG activity

Pinard, E. et al. (2010) Discovery of benzoylisoindolines as a novel class of potent, selective and orally active GlyT1 inhibitors. Bioorg Med Chem Lett 20 (23), 6960-6965

ND

Nguyen, H.N. et al. (2012) Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists. Bioorg Med Chem Lett 22 (2), 1055-1060

Removal of methyl groups from core reduces hERG activity

Chakka, N. et al. (2012) Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Na(v)1.7 antagonists. Bioorg Med Chem Lett 22 (5), 2052-2062

ND

Packiarajan, M. et al. (2012) N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators. Bioorg Med Chem Lett 22 (17), 5658-5662

Nitrogen in aromatic ring reduces hERG activity

Andaloussi, M. et al. (2013) A novel series of histamine H4 receptor antagonists based on the pyrido[3,2-d]pyrimidine scaffold: comparison of hERG binding and target residence time with PF-3893787. Bioorg Med Chem Lett 23 (9), 2663-2670

Remove fluorines on rings, add carboxyl

Cavalli, A. et al. (2012) Computational design and discovery of “minimally structured” hERG blockers. J Med Chem 55 (8), 4010-4014

ND

Finlay, H.J. et al. (2012) Discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydro pyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)metha none as a potent and selective I(Kur) inhibitor. J Med Chem 55 (7), 3036-3048

2 comments

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  1. Abhik Seal says:

    This is cool !! Why not build a set of smarts filters for hERG?

    1. sean says:

      May take more than SMARTS..over a decade of modeling (small molecule and large molecule) and I am not convinced (based on the fact companies are not sharing their predictions in J MED CHEM and other papers – just lots of in vitro data) we are there yet. So far every algorithm and descriptor has been thrown at hERG. This small table is just the tip of the iceberg in terms of SAR out there. The only way to really learn anything here is to combine insights from all the different labs and models/methods used IMHO and thats going to take more effort than this post.

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