Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor.

Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600.

Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist.

Overactivation of the mineralocorticoid receptor (MR) is involved in many diseases, such as hypertension, kidney disease, and heart failure. Thus, MR antagonists (MRAs) are expected to be beneficial to patients with these diseases. In order to identify novel nonsteroidal MRAs that overcome the issues of already marketed steroidal MRAs, we searched for new compounds guided by our hypothesis that T-shaped compounds with a hydrophobic core structure, two polar functional groups at both extremities able to interact with MR, and a bulky substituent that can interfere with the folding of the C-terminal helix 12 may exhibit antagonist activity toward MR.

Effect of Water Molecules on the Activating S810L Mutation of the Mineralocorticoid Receptor.

The mineralocorticoid receptor (MR) is a nuclear receptor whose endogenous ligands are mineralocorticoids, a type of steroid hormone. The activating S810L mutation is known to cause severe early-onset and pregnancy-related hypertension. Progesterone binds to the wild-type (WT) MR as a passive antagonist with fast dissociation; however, it binds to the S810L mutant as a full agonist with slow dissociation.

Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety.

We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A.

Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2.

It is necessary for aldosterone synthase (CYP11B2) inhibitors to have both high potency and high selectivity over 11β-hydroxylase (CYP11B1), a critical enzyme for cortisol synthesis. Previous studies have reported a number of CYP11B2 inhibitors, most of which have an imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2; however, highly selective inhibitors of human CYP11B2 are still needed. To expand the selectivity in humans, we explored alternative templates and found that pyrazoles were suitable templates for CYP11B2 inhibitors.

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms.

Prediction of the binding affinity of compounds with diverse scaffolds by MP-CAFEE.

Accurate methods to predict the binding affinities of compounds for target molecules are powerful tools in structure-based drug design (SBDD). A recently developed method called massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) successfully predicted the binding affinities of compounds with relatively similar scaffolds. We investigate the applicability of MP-CAFEE for predicting the affinity of compounds having more diverse scaffolds for the target p38α, a mitogen-activated protein kinase.

Combination of virtual screening and high throughput gene profiling for identification of novel liver X receptor modulators.

We conducted virtual docking studies using GLIDE with modified LXRbeta ligand-binding domain (LBD) on internal compound collection followed by the gene profiling with ArrayPlate mRNA assay. A total of 69 compounds were found to upregulate LXRalpha and certain LXR regulated genes from 1308 compounds selected by virtual screen (hit rate: 5.3%).

Discovery and structure-activity relationship studies of indole derivatives as liver X receptor (LXR) agonists.

A structurally novel liver X receptor (LXR) agonist (1) was identified from internal compound collection utilizing the combination of structure-based virtual screening and high-throughput gene profiling. Compound 1 increased ABCA1 gene expression by eightfold and SREBP1c by threefold in differentiated THP-1 macrophage cell lines. Confirmation of its agonistic activity against LXR was obtained in the co-factor recruitment and reporter transactivation assays.

Classification of chemical compounds by protein-compound docking for use in designing a focused library.

We developed a new method for the classification of chemical compounds and protein pockets and applied it to a random screening experiment for macrophage migration inhibitory factor (MIF). The principal component analysis (PCA) method was applied to the protein-compound interaction matrix, which was given by thorough docking calculations between a set of many protein pockets and chemical compounds. Each compound and protein pocket was depicted as a point in the PCA spaces of compounds and proteins, respectively.