Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for Mouse Studies.

Decreased activity and expression of the G-protein coupled receptor GPR88 is linked to many behavior-linked neurological disorders. Published preclinical GPR88 allosteric agonists all have pharmacokinetic properties that preclude their progression to the clinic, including high lipophilicity and poor brain penetration. Here, we describe our attempts to improve GPR88 agonists' drug-like properties and our analysis of the trade-offs required to successfully target GPR88's allosteric pocket.

Hybrid Screening Approach for Very Small Fragments: X-ray and Computational Screening on FKBP51.

Fragment-based drug discovery (FBDD) permits efficient sampling of the vast chemical space for hit identification. Libraries are screened biophysically and fragment:protein co-structures are determined by X-ray crystallography. In parallel, computational methods can derive pharmacophore models or screen virtual libraries.

Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators.

The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30 mg/kg oral dose.

Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice.

Background: Forty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects.

Identification of a potent sodium hydrogen exchanger isoform 1 (NHE1) inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat.

Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure.

An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction.

A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.

Differential effects of immunophilin-ligands (FK506 and V-10,367) on survival and regeneration of rat retinal ganglion cells in vitro and after optic nerve crush in vivo.

Immunophilins belong to the large family of peptidyl-prolyl-cis-trans-isomerases known to be involved in many cellular processes (e.g., protein trafficking and transcriptional regulation).

A Novel Phenylene Topology: Total Syntheses of Zigzag [4]- and [5]Phenylene.

In agreement with theory, the title compounds 1 and 2, which were prepared by CpCo-catalyzed cycloisomerizations of appropriate oligoalkynylbenzenes, display physical properties that are in contrast with those of the corresponding linear isomers, but that are very similar to those of the angular topomers.