Heinrich Meier

Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits

Drug-like and lead-like hits derived from HTS campaigns provide good starting points for lead optimization. However, too strong emphasis on potency as hit-selection parameter might hamper the success of such projects. A detailed absorption, distribution, metabolism, excretion and toxicology (ADME-Tox) profiling is needed to help identify hits with a minimum number of (known) liabilities. This is particularly true for drug-like hits. Herein, we describe how to break down large numbers of screening hits and we provide a comprehensive overview of the strengths and weaknesses for each structural class. The overall profile (e.g. ligand efficiency, selectivity and ADME-Tox) is the distinctive feature that will define the priority for follow-up.

In Silico ADMET Traffic Lights as a Tool for the Prioritization of HTS Hits

The need for inu2005silico characterization of HTS hit structures as part of a data‐driven hit‐selection process is demonstrated. A solution is described in the form of an inu2005silico ADMET traffic light and PhysChem scoring system. This has been extensively validated with in‐house data at Bayer, published data, and a collection of launched small‐molecule oral drugs.

Naphthol derivatives as TRPV1 inhibitors for the treatment of urinary incontinence.

We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystometry models of urinary incontinence after intravenous administration.

Diversity-oriented synthesis of substituted pyrazolo〔4,3-d〕〔1,2,3〕triazin-4-ones

An efficient synthesis of 3,7-disubstituted 3,5-dihydro-4H-pyrazolo-[4,3-d][1,2,3]triazin-4-ones (2), especially suited for late-stage decoration, is described. Diverse 3-benzyl analogs were obtained by amidation-cyclization in one pot and various pyrazolotriazinone-7-bromides were employed in Suzuki and Sonogashira cross-coupling reactions.