Klaus Urbahns

Selective intermediate-/small-conductance calcium-activated potassium channel (KCNN4) blockers are potent and effective therapeutics in experimental brain oedema and traumatic brain injury caused by acute subdural haematoma

Early deterioration and death after brain injury is often the result of oedema in the injured and peri‐lesional tissue. So far, no pharmacotherapy is available that exhibits significant brain oedema‐reducing efficacy in patients. We selected two low molecular weight compounds from different chemical classes, a triazole (1‐[(2‐chlorophenyl)diphenylmethyl]‐1,2,3‐triazole) and a cyclohexadiene (methyl 4‐[4‐chloro‐3‐(trifluoromethyl)phenyl]‐6‐methyl‐3‐oxo‐1,4,7‐tetrahydroisobenzofuran‐5‐carboxylate) to characterize their pharmacological properties on KCNN4 channels (intermediate/small conductance calcium‐activated potassium channel, subfamily N, member 4) in vitro as well as in vivo. In vitro we replaced potassium by rubidium (Rb+) and determined Rb+ fluxes evoked by 10 µm of the calcium ionophore A23187 on C6BU1 rat glioma cells. Compared with known KCNN4 blockers, such as clotrimazole (IC50 = 360 ± 12 nm) and charybdotoxin (IC50 = 3.3 ± 1.9 nm), the triazole and cyclohexadiene were considerably more potent than clotrimazole and displayed similar potencies (IC50 = 12.1 ± 8.8 and 13.3 ± 4.7 nm, respectively). In the rat acute subdural haematoma model, both the triazole and cyclohexadiene displayed reduction of brain water content (−26% at 0.3 mg/kg and −24% at 0.01 mg/kg) and reduction of the intracranial pressure (−46% at 0.1 mg/kg and −60% at 0.003 mg/kg) after 24 h when administered as a 4‐h infusion immediately after brain injury. When infarct volumes were determined after 7 days, the triazole as well as the cyclohexadiene displayed strong neuroprotective efficacy (−52% infarct volume reduction at 1.2 mg/kg and −43% at 0.04 mg/kg, respectively). It is concluded that blockade of KCNN4 channels is a new pharmacological approach to attenuate acute brain damage caused by traumatic brain injury.

4-Phenyl-4H-pyrans as IKCa channel blockers

4-Phenyl-4H-pyrans have been identified as potent and specific IK(Ca) channel blockers. Their synthesis and structure-activity relationships are described. A selected derivative, rac-11, reduces the infarct volume in a rat subdural hematoma model of traumatic brain injury after iv administration.

Biphenyls as Potent Vitronectin Receptor Antagonists. Part 2: Biphenylalanine Ureas

Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated in a variety of disease states, like restenosis, osteoporosis and cancer. In this work, we present the development of a novel class of biphenyl vitronectin receptor antagonists. Identified from a focused combinatorial library based on para-bromo phenylalanine, these compounds show nanomolar affinity to the vitronectin receptor and display unprecedented SAR. Their binding mode can be rationalized by computational docking studies using the X-ray structure of alpha(V)beta(3).

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.

Tetrahydro-naphthols as orally available TRPV1 inhibitors.

Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the leads phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level.