Corinna Grisostomi

Design and Preparation of Potent, Nonpeptidic, Bioavailable Renin Inhibitors

Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.

Piperidine-based renin inhibitors: upper chain optimization.

The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK-1597), a renin inhibitor with a suitable profile for development is described.

Design and optimization of new piperidines as renin inhibitors

The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.

Inhibitors of aspartic proteases – potential antimalarial agents

This review emphasises the importance of research in the field of new antimalarial therapeutic agents, summarises the biology of plasmepsin II, a protozoal aspartic protease, and other related plasmepsins, and analyses the scientific literature and the patent literature describing efforts in the search for inhibitors of plasmepsins. As there are only very limited efforts in this area by the pharmaceutical industry, the patent literature reviewed covers the period of the last 10 years and, in addition, the article discusses results published by academic research groups. Several approaches are based on earlier work in the field of HIV-1 protease inhibitors and of renin inhibitors.

New classes of potent and bioavailable human renin inhibitors

New classes of de novo designed renin inhibitors are reported. Some of these compounds display excellent in vitro and in vivo activities toward human renin in a TGR model. The synthesis of these new types of mono- and bicyclic scaffolds are reported, and properties of selected compounds discussed.

Preparation, Antiepileptic Activity, and Cardiovascular Safety of Dihydropyrazoles as Brain-Penetrant T-Type Calcium Channel Blockers

A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.

Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action

More than 40 % of the worlds population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub‐Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine‐based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT‐451840 [(S,E)‐N‐(4‐(4‐acetylpiperazin‐1‐yl)benzyl)‐3‐(4‐(tert‐butyl)phenyl)‐N‐(1‐(4‐(4‐cyanobenzyl)piperazin‐1‐yl)‐1‐oxo‐3‐phenylpropan‐2‐yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy.

Inhibitors of plasmepsin II: Potential antimalarial agents

In order to overcome the problem of drug resistance in malaria, it appears wise to concentrate drug discovery efforts toward new structural classes and new mechanisms of action. We report our results, targeting Plasmepsin II, a Plasmodium falciparum aspartic protease active in hemoglobin degradation, a parasite specific catabolic pathway. The results show that the new structural class is not only inhibiting PMII in vitro but is also active in a P. falciparum infected human red blood cell assay.

Milestones to the Discovery of T-type Calcium Channel Blockers for the Treatment of Generalized Epilepsies

We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.