Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure-Kinetic Relationships.

We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles.

Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer.

Practical application of 3-substituted-2,6-difluoropyridines in drug discovery: Facile synthesis of novel protein kinase C theta inhibitors.

We previously reported a facile preparation method of 3-substituted-2,6-difluoropyridines, which were easily converted to 2,3,6-trisubstituted pyridines by nucleophilic aromatic substitution with good regioselectivity and yield. In this study, we demonstrate the synthetic utility of 3-substituted-2,6-difluoropyridines in drug discovery via their application in the synthesis of various 2,3,6-trisubstituted pyridines, including macrocyclic derivatives, as novel protein kinase C theta inhibitors in a moderate to good yield. This synthetic approach is useful for the preparation of 2,3,6-trisubstituted pyridines, which are a popular scaffold for drug candidates and biologically attractive compounds.

Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors - Part 3.

Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the pKa value of the acidic moiety.

Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors-Part 2.

Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood-brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs.

Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent and selective PKCθ inhibitors.

A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-θ (PKCθ) inhibitor. Using the docking model of compound 1 bound to PKCθ as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e.

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor.

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats.

Discovery of a novel acyl-CoA: cholesterol acyltransferase inhibitor: the synthesis, biological evaluation, and reduced adrenal toxicity of (4-phenylcoumarin)acetanilide derivatives with a carboxylic acid moiety.

As a part of our research for novel potent and orally available acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors that can be used as anti-atherosclerotic agents, we recently reported the discovery of the (4-phenylcoumarine)acetanilide derivative 1. However, compound 1 showed adrenal toxicity in animal models. In order to search for safer ACAT inhibitors that do not have adrenal toxicity, we examined the inhibitory activity of ACAT in human macrophage and adrenal cells.

Discovery of a potent and orally available acyl-CoA: cholesterol acyltransferase inhibitor as an anti-atherosclerotic agent: (4-phenylcoumarin)acetanilide derivatives.

Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified.

A novel coenzyme A:diacylglycerol acyltransferase 1 inhibitor stimulates lipid metabolism in muscle and lowers weight in animal models of obesity.

Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final and only committed step in triacylglycerol synthesis. In this report, we describe the pharmacological effects of a novel selective DGAT1 inhibitor, Compound-A.

Coenzyme A: diacylglycerol acyltransferase 1 inhibitor ameliorates obesity, liver steatosis, and lipid metabolism abnormality in KKAy mice fed high-fat or high-carbohydrate diets.

Coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of the 2 known DGAT enzymes that catalyze the final and only committed step in triacylglycerol synthesis; this enzyme is considered to be a potential therapeutic target in metabolic disorders such as obesity and its related lipid abnormalities. Compound-Z, a novel specific small-molecule DGAT1 inhibitor, significantly reduced adipose tissue weight and tended to hepatic lipid accumulation in genetically obese KKAy mice. These actions were shown to almost the same extent in both a high-fat feeding condition in which triacylglycerols are synthesized mainly via exogenous fatty acid and a low-fat, high-carbohydrate feeding condition in which triacylglycerols are synthesized mainly via de novo fatty acid synthesis.

Novel acyl coenzyme A: diacylglycerol acyltransferase 1 inhibitors-synthesis and biological activities of N-(substituted heteroaryl)-4-(substituted phenyl)-4-oxobutanamides.

In a program to discover new small molecule diacylglycerol acyltransferase (DGAT)-1 inhibitors, screening of our in-house chemical library was carried out using recombinant human DGAT-1 enzyme. From this library, the lead compound 1a was identified as a new class of DGAT-1 inhibitor. A series of novel N-(substituted heteroaryl)-4-(substituted phenyl)-4-oxobutanamides 2 was designed from 1a, synthesized and evaluated for inhibitory activity against DGAT-1 enzyme.

Novel acyl coenzyme A (CoA): diacylglycerol acyltransferase-1 inhibitors: synthesis and biological activities of diacylethylenediamine derivatives.

A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.