Kyu Yang Yi

The orally active urotensin receptor antagonist, KR36676, attenuates cellular and cardiac hypertrophy

Blockade of the actions of urotensin‐II (U‐II) mediated by the urotensin (UT) receptor should improve cardiac function and prevent cardiac remodelling in cardiovascular disease. Here, we have evaluated the pharmacological properties of the recently identified UT receptor antagonist, 2‐(6,7‐dichloro‐3‐oxo‐2H‐benzo[b][1,4]oxazin‐4(3H)‐yl)‐N‐methyl‐N‐(2‐(pyrrolidin‐1‐yl)‐1‐(4‐(thiophen‐3‐yl)phenyl) ethyl)acetamide (KR36676).

4-arylphthalazin-1(2H)-one derivatives as potent antagonists of the melanin concentrating hormone receptor 1 (MCH-R1).

A novel series of 4-arylphthalazin-1(2H)-one linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of an extensive SAR study probing the effects of substituents on the 4-arylphthalazin-1(2H)-one C-4 aryl group led to the identification of the 4-(3,4-difluorophenyl) derivative as a highly potent MCH-R1 inhibitor with an IC(50)=1nM. However, further investigations showed that this substance has unacceptable pharmacokinetic properties including a high clearance and volume of distribution.

Synthesis and SAR investigations of novel 2-arylbenzimidazole derivatives as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists

Compounds containing 2-arybenzimidazole ring systems linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of structure-activity relationship studies led to the identification of compound 4c as a potent MCH-R1 antagonist (IC(50)=1 nM). This compound also has good metabolic stability, and favorable pharmacokinetic and brain penetration properties. However 4c was found to be potent inhibitor of the hERG potassium channel.

Synthesis and SAR of thieno(3,2-b)pyridinyl urea derivatives as urotensin-II receptor antagonists

The preparation and SAR profile of thieno[3,2-b]pyridinyl urea derivatives as novel and potent urotensin-II receptor antagonists are described. An activity optimization study, probing the effects of substituents on thieno[3,2-b]pyridinyl core and benzyl group of the piperidinyl moiety, led to the identification of p-fluorobenzyl substituted thieno[3,2-b]pyridinyl urea 6n as a highly potent UT antagonist with an IC50 value of 13nM. Although 6n displays good metabolic stability and low hERG binding activity, it has an unacceptable oral bioavailability.

Discovery of novel scaffolds for Rho kinase 2 inhibitor through TRFRET-based high throughput screening assay.

Recent advances in basic and clinical studies have identified Rho kinase (ROCK) as an important target potentially implicated in a variety of cardiovascular diseases and ROCK inhibitors were considered as a pharmacological strategy to prevent and treat cardiovascular diseases. To screen the small molecule compound library against ROCK, a high throughput screening (HTS) campaign was carried out using immobilized metal affinity for phosphochemicals (IMAP)-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Z value and signal to background (S/B) ratio were achieved at 0.76 and 5.27 for the pilot library screening of the most diverse set consisting of 15,040 compounds with a reasonable reconfirmation rate. From this screening campaign, four novel scaffolds, such as 3- nitropyridine, 4-methoxy-1,3,5,-triazine, naphthalene-1,4-dione, and 2,3-dihydro-1H-pyrrolo[2,3-b]quinoxaline, were yielded. Particularly, we found that 3-nitropyridine derivatives possess potent inhibitory activity and selectivity for ROCK. Our findings provide important information for the design of novel ROCK inhibitor.

Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on ischemia and reperfusion-induced myocardial infarction in rats and dogs.

The present study was performed to evaluate the cardioprotective effects of KR‐33028, a novel Na+/H+ exchanger subtype 1 (NHE‐1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45‐min coronary occlusion and a 90‐min reperfusion, KR‐33028 at 5u2003min before occlusion (i.v. bolus) dose‐dependently reduced myocardial infarct size from 58.0% to 46.6%, 40.3%, 39.7%, 33.1%, and 27.8% for 0.03, 0.1, 0.3, 1.0, and 3.0u2003mg/kg respectively (Pu2003<u20030.05). In anesthetized beagle dogs that underwent a 1.0‐h occlusion followed by a 3.0‐h reperfusion, KR‐33028 (3u2003mg/kg, i.v. bolus) markedly decreased infarct size from 45.6% in vehicle‐treated group to 16.4% (Pu2003<u20030.05), and reduced the reperfusion‐induced release in creatine kinase myocardial band isoenzyme (MB), lactate dehydrogenase, troponin‐I, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. In separate experiments to assess the effects of timing of treatment, KR‐33028 (1u2003mg/kg, i.v. bolus) given 10u2003min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (46.3% and 44.1% respectively) compared with vehicle‐treated group. In all studies, KR‐33028 caused no significant changes in any hemodynamic profiles. In an isolated rat heart model of hypothermic cardioplegia, KR‐33028 (30u2003μm), which was added to the heart preservation solution (histidin–tryptophan–ketoglutarate) during hypothermic cardioplegic arrest, significantly improved the recovery of left ventricular developed pressure, heart rate and dP/dtmax after reperfusion. Taken together, these results indicate that KR‐33028 significantly reduced the myocardial infarction induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles.

Synthesis and SAR study of pyrrolo[3,4-b]pyridin-7(6H)-one derivatives as melanin concentrating hormone receptor 1 (MCH-R1) antagonists

The discovery and optimization of novel pyrrolo[3,4-b]pyridin-7(6H)-one MCH-R1 antagonists are described. A systematic SAR study probing the effects of aryl-, benzyl- and arylthio-substituents at the 2-position of the pyrrolo[3,4-b]pyridin-7(6H)-ones led to identification of the 2-[(4-fluorophenyl)thio] derivative 7b as a highly potent MCH-R1 antagonist. This compound also has favorable pharmacokinetic properties along with a high metabolic stability and a minimal impact on CYP isoforms and hERG.

Predicted Ligands for the Human Urotensin‐II G Protein‐Coupled Receptor with Some Experimental Validation

Human Urotensin‐II (U‐II) is the most potent mammalian vasoconstrictor known. 1 Thus, a U‐II antagonist would be of therapeutic value in a number of cardiovascular disorders. 2 Here, we describe our work on the prediction of the structure of the human U‐II receptor (hUT2R) using GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) complete sampling Monte Carlo method. With the validation of our predicted structures, we designed a series of new potential antagonists predicted to bind more strongly than known ligands. Next, we carried out R‐group screening to suggest a new ligand predicted to bind with 7u2005kcalu2009mol−1 better energy than 1‐{2‐[4‐(2‐bromobenzyl)‐4‐hydroxypiperidin‐1‐yl]ethyl}‐3‐(thieno[3,2‐b]pyridin‐7‐yl)urea, the designed antagonist predicted to have the highest affinity for the receptor. Some of these predictions were tested experimentally, validating the computational results. Using the pharmacophore generated from the predicted structure for hUT2R bound to ACT‐058362, we carried out virtual screening based on this binding site. The most potent hit compounds identified contained 2‐(phenoxymethyl)‐1,3,4‐thiadiazole core, with the best derivative exhibiting an IC50 value of 0.581u2005μM against hUT2R when tested inu2005vitro. Our efforts identified a new scaffold as a potential new lead structure for the development of novel hUT2R antagonists, and the computational methods used could find more general applicability to other GPCRs.

A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure

Abstract Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N‐(1‐(3‐bromo‐4‐(piperidin‐4‐yloxy)benzyl)piperidin‐4‐yl)benzo[b]thiophene‐3‐carboxamide (KR‐36996), in experimental models of heart failure. KR‐36996 displayed a high binding affinity (Ki=4.44±0.67 nM) and selectivity for urotensin II receptor. In cell‐based study, KR‐36996 significantly inhibited urotensin II‐induced stress fiber formation and cellular hypertrophy in H9c2UT cells. In transverse aortic constriction‐induced cardiac hypertrophy model in mice, the daily oral administration of KR‐36996 (30 mg/kg) for 14 days significantly decreased left ventricular weight by 40% (P<0.05). In myocardial infarction‐induced chronic heart failure model in rats, repeated echocardiography and hemodynamic measurements demonstrated remarkable improvement of the cardiac performance by KR‐36996 treatment (25 and 50 mg/kg/day, p.o.) for 12 weeks. Moreover, KR‐36996 decreased interstitial fibrosis and cardiomyocyte hypertrophy in the infarct border zone. These results suggest that potent and selective urotensin II receptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR‐36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications.

A urotensin II receptor antagonist, KR36676, decreases vascular remodeling and inflammation in experimental pulmonary hypertension

The pathophysiological implications of binding of urotensin II (U-II) to urotensin II receptor (UT) in pulmonary arterial hypertension (PAH) have been proposed recently. Besides high expression of U-II in experimental models and patients with PAH, U-II has been shown to increase proliferation of pulmonary vascular smooth muscle cells and inflammatory responses, which were critical for PAH pathophysiology. However, the direct role of the urotensinergic system in the pathogenesis of PAH is yet to be understood. The aim of the present study was to determine whether a novel UT antagonist, KR36676, attenuates the pathophysiological progression of PAH in an animal model of PAH. PAH was induced by a single subcutaneous injection of monocrotaline (MCT, 60mg/kg) in rats. All the animals received KR36676 (30mg/kg/day) or vehicle by oral gavage. Three weeks after MCT-injection, changes in hemodynamic parameters, extent of right ventricular hypertrophy, fibrosis and pulmonary vascular remodeling, and degree of protein expression were determined. Oral administration of KR36676 effectively decreased the MCT-induced increase in right ventricular systolic pressure, hypertrophy and fibrosis. Furthermore, wall thickness of pulmonary arterioles, proliferation of pulmonary vascular cells, and inflammatory response significantly decreased in the KR36676-treated group following MCT injection compared to that in the MCT-treated vehicle group. These preventive effects of KR36676 are mediated, at least in part, by suppression of ERK1/2 and NF-κB signaling pathways. The novel UT antagonist, KR36676, effectively prevented MCT-induced PAH progression and pulmonary vascular remodeling in rat model. Our findings support the therapeutic efficacy of UT antagonist in PAH prevention and elucidate the possible underlying mechanisms of action.