Optimization of halopemide for phospholipase D2 inhibition.

Halopemide, which was identified by HTS to inhibit phospholipase D2 (PLD2), provided the basis for an exploratory effort to identify potent inhibitors of PLD2 for use as inflammatory mediators. Parallel synthesis and purification were utilized to rapidly identify orally available amide analogs derived from indole 2-carboxylic acids with superior potency versus PLD2

Design of thioether cyclic peptide scaffolds with passive permeability and oral exposure

Advances in the design of permeable peptides and in the synthesis of large arrays of macrocyclic peptides with diverse amino acids have evolved on parallel, but independent tracks. Less precedence combines their respective attributes, in turn limiting potential to identify permeable peptide ligands for key protein targets. Herein, we present one strategy for focusing the powerful ligand-finding capability of DNA- or RNA-templated peptide synthesis within permeability-biased property space. Despite higher than standard molecular weights (from 774 to 1076 g·mol-1), the 6-, 7-, and 8-mer cyclic peptides of the present contribution are partially N-methylated to achieve low energy conformations with low desolvation penalties. The N-methylation patterns were selected using in silico methods, then experimentally validat-ed with high passive permeability and oral exposure. Further, the present work shows that chemical structures that overlap the synthetic capabilities of DNA- or RNA-templated peptide syntheses in water, can be both permeable and orally exposed. We envision that, by retaining the backbone N-methylation pattern and consequent bias toward per-meability, one can generate large peptide arrays with sufficient side chain diversity to identify permeability-biased lig-ands to a variety of protein targets

2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes

The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes alpha, betaI, delta, epsilon, eta and theta (in particular PKCdelta, epsilon, eta and theta), and display a 10-100 fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCtheta-dependent pathways in vitro and in vivo. In vitro, a-CD3/a-CD28-induced lymphocyte proliferation could be effectively blocked in 10 % rat whole blood. In mice, 11 dose-dependently inhibited Staphylococcus aureus enterotoxin B-triggered IL-2 serum levels after oral dosing

Clearance of plasma PCSK9 via the asialoglycoprotein receptor mediated by heterobifunctional ligands.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting the degradation of hepatic LDL receptors (LDLRs). Current therapeutic approaches use antibodies that disrupt PCSK9 binding to LDLR to reduce circulating LDL-C concentrations or siRNA that reduces PCSK9 synthesis and thereby levels in circulation. Recent reports describe small molecules that, like therapeutic antibodies, interfere with PCSK9 binding to LDLR. We report an alternative approach to decrease circulating PCSK9 levels by accelerating PCSK9 clearance and degradation using heterobifunctional molecules that simultaneously bind to PCSK9 and the asialoglycoprotein receptor (ASGPR). Various formats, including bispecific antibodies, antibody-small molecule conjugates, and heterobifunctional small molecules, demonstrate binding in vitro and accelerated PCSK9 clearance in vivo. These molecules showcase a new approach to PCSK9 inhibition, targeted plasma protein degradation (TPPD), and demonstrate the feasibility of heterobifunctional small molecule ligands to accelerate the clearance and degradation of pathogenic proteins in circulation

Preliminary Studies of 3,5-Diarylazoles as Novel and Selective Inhibitors of Protein Kinase D

Preliminary studies of the SAR of novel 3,5-diarylazole inhibitors of Protein Kinase D (PKD) are reported. Notably, compounds bearing an α-aminonitrile moiety have been found to be active in cellular assays of HDAC5 nuclear localization, orally biovailable, and highly selective versus a panel of additional putative histone deacetylase (HDAC) kinases, providing potential tools for the further study of PKD / HDAC5 signalin

Discovery and in vivo evaluation of potent dual CYP11B2 (aldosterone synthase) and CYP11B1 inhibitors

ABSTRACT: Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing’s syndrome

Evolution of Novartis' Small Molecule Screening Deck Design

This article summarizes the evolution of the screening deck at the Novartis Institutes for BioMedical Research (NIBR). Historically, the screening deck was an assembly of all available compounds. In 2015, we designed a first deck to facilitate access to diverse subsets with optimized properties. We allocated the compounds as plated subsets on a 2D grid with property based ranking in one dimension and increasing structural redundancy in the other. The learnings from the 2015 screening deck were applied to the design of a next generation in 2019. We found that using traditional leadlikeness criteria (mainly MW, clogP) reduces the hit rates of attractive chemical starting points in subset screening. Consequently, the 2019 deck relies on solubility and permeability to select preferred compounds. The 2019 design also uses NIBR's experimental assay data and inferred biological activity profiles in addition to structural diversity to define redundancy across the compound sets

Identification of Potent and Selective Aminobipyridyl Inhibitors of Protein Kinase D

The synthesis and biological evaluation of potent and selective PKD inhibitors is described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein