Sandra L. Cockerham

Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure

Cholesteryl ester transfer protein (CETP) catalyses the exchange of cholesteryl ester and triglyceride between HDL and apoB containing lipoprotein particles. The role of CETP in modulating plasma HDL cholesterol levels in humans is well established and there have been significant efforts to develop CETP inhibitors to increase HDL cholesterol for the treatment of coronary artery disease. These efforts, however, have been hampered by the fact that most CETP inhibitors either have low potency or have undesirable side effects. In this study, we describe a novel benzazepine compound evacetrapib (LY2484595), which is a potent and selective inhibitor of CETP both in vitro and in vivo. Evacetrapib inhibited human recombinant CETP protein (5.5 nM IC50) and CETP activity in human plasma (36 nM IC50) in vitro. In double transgenic mice expressing human CETP and apoAI, evacetrapib exhibited an ex vivo CETP inhibition ED50 of less than 5 mg/kg at 8 h post oral dose and significantly elevated HDL cholesterol. Importantly, no blood pressure elevation was observed in rats dosed with evacetrapib at high exposure multiples compared with the positive control, torcetrapib. In addition, in a human adrenal cortical carcinoma cell line (H295R cells), evacetrapib did not induce aldosterone or cortisol biosynthesis whereas torcetrapib dramatically induced aldosterone and cortisol biosynthesis. Our data indicate that evacetrapib is a potent and selective CETP inhibitor without torcetrapib-like off-target liabilities. Evacetrapib is currently in phase II clinical development.

Pulmonary actions of anandamide, an endogenous cannabinoid receptor agonist, in guinea pigs.

Anandamide (arachidonylethanolamide), 5,8,11,14-eicosatetraenamide, (N-2-hydroxyethyl), was tested for bronchodilator and anti-inflammatory activities. Conscious guinea pigs were given cumulative i.v. doses of anandamide (1.0, 3.0, and 10.0 mg/kg) to assess its effect on dynamic compliance (Cdyn), total pulmonary resistance (RL), tidal volume (VT) and breathing frequency (f). Other guinea pigs were exposed to an aerosol of A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid) until Cdyn decreased by 50% (approximately 5 min) and at 20 min, cumulative i.v. doses of anandamide (1.0, 3.0, and 10.0 mg/kg) were administered and reversal of Cdyn examined. After the final dose of anandamide, the animals were killed and excised lung gas volumes (ELGV), i.e., pulmonary gas trapping, measured. Other animals were treated i.v. with anandamide (10.0 mg/kg), exposed to an aerosol of A23187 until labored breathing began, and then killed 1 h later. Anandamide did not significantly affect Cdyn, RL, VT and f. ELGV values of anandamide-treated guinea pigs were not different from those of vehicle-treated animals. Anandamide failed to reverse A23187-induced decreases in Cdyn and to reduce A23187-associated ELGV increases. Also, it did not prevent the prolonged airway obstruction caused by A23187. Histological evaluation revealed that anandamide significantly reduced A23187-related airway epithelial injury and pulmonary leukocytosis. However, it did not prevent A23187-induced peribronchiolar granulocytic accumulation. Our results suggest that in vivo anandamide has minimal direct airway smooth muscle-related actions, however it may possess modest anti-inflammatory properties.

Design, synthesis and structure-activity-relationship of 1,5-tetrahydronaphthyridines as CETP inhibitors.

This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.

Pulmonary actions of LY255283, a leukotriene B4 receptor antagonist

The actions of LY255283, a leukotriene (LT) B4 receptor antagonist, were examined on guinea pig lung. LTB4 and LY255283 displaced [3H]LTB4 from its binding site on lung membranes with pKi values of 9.9 and 7.0, respectively. In the functional correlate of the binding studies, LY255283 competitively reduced contractile responses of lung parenchyma to LTB4 (pA2 = 7.2). LTB4 produced airway obstruction which was reduced by LY255283 administered i.v. (ED50 = 2.8 mg/kg) or orally (ED50 = 11.0 mg/kg). Contractile responses to histamine, LTD4 and the thromboxane mimetic, U46619, were not reduced by LY255283. The compound also did not inhibit cyclooxygenase or 5-lipoxygenase enzymes. We conclude that LY255283 selectively antagonized pharmacologic responses to LTB4 on lung tissue and appears to be a useful tool to investigate the role of LTB4 in pulmonary disease.

Effect of dexamethasone on A23187-induced airway responses in the guinea pig.

We examined the effect of dexamethasone on A23187-induced bronchospasm, pulmonary inflammation and airway responses to substance P. Guinea pigs, dosed orally once a day for 4 days with dexamethasone (3.0, 10.0 or 30.0 mg/kg) or saline, were exposed to an aerosol of A23187 for 12 min or until labored breathing began. Postmortem pulmonary gas trapping was used as an indicator of in vivo airway obstruction and changes in bronchial responses. Dexamethasone did not alter airway obstruction or inflammation 1 h after A23187 exposure. However, dexamethasone reduced the enhanced airway responses to substance P and bronchiolar/peribronchiolar inflammation 24 h post-A23187. It is possible that glucocorticosteroid suppression of A23187-induced pulmonary inflammation was important in reducing the increased airway responses to substance P.

-alkoxyphenol leukotriene B4 receptor antagonists: effect of a chroman carboxylic acid.

Abstract Several ortho -alkoxyphenols containing a chroman carboxylic acid sidechain have been prepared as antagonists of leukotriene B4 receptors. These antagonists were compared to their parent alkoxyphenols containing the tetrazole acid sidechain. These chroman containing antagonists retained their binding potency for human neutrophil receptors; however, showed enhanced potency against guinea pig receptors in both in vitro and in vivo systems.

alkoxyphenol leukotriene B4 receptor antagonists

Abstract A series of ortho -alkoxyphenols containing a tetrazole acid sidechain have been prepared as antagonists of leukotriene B4 receptors. These compounds were tested as receptor antagonists of human neutrophil and guinea pig lung membrane leukotriene B4 receptors. Compounds in this series were found to be up to 18-fold more potent than LY255283. These results indicate that the acyl group of the 1,2,4,5 substituted hydroxyacetophenone class of LTB4 antagonists is not critical to antagonist potency.

Design and synthesis of new tetrahydroquinolines derivatives as CETP inhibitors

This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.

QUINOLINE-SUBSTITUTED DIHYDROINDOLES AS CYSLT1 (LTD4 RECEPTOR) ANTAGONISTS

Abstract A series of quinoline-substituted dihydroindoles has been synthesized and evaluated as antagonists of the cysLT 1 receptor. This series, exemplified by 2 (LY302905; pKi = 8.3 for inhibition of binding of 3 H-LTD 4 to guinea pig lung membranes), represents reduced analogues of the corresponding indoles that were previously shown to be potent, orally active cysLT 1 receptor antagonists. These dihydroindole compounds generally displayed increased in vitro and in vivo (oral) activity.

Aerosolized LTB4 produces delayed onset increases in pulmonary gas trapping

Airway obstruction, as measured by increases in postmortem pulmonary gas trapping, and lung inflammatory changes were examined in guinea pigs exposed for up to 4 h to aerosols of leukotriene B4 (LTB4) or its non-chemotactic isomer, 6-trans-12-epi-LTB4. Airway obstruction and cytological responses in isomer-exposed animals were similar to those of unexposed control animals. LTB4-exposed animals had minimal inflammatory changes at 0.5 h but became dyspneic by 2 h and had increased airway obstruction, bronchoalveolar lavage neutrophils and eosinophils, and pulmonary tissue granulocyte scores. The LTB4-induced effects at 4 h were similar to those 2 h, except for further increase in BAL neutrophils and eosinophils. LTB4-induced airway obstructive and inflammatory changes were prevented by pretreatment with the LTB4 receptor antagonist SC-41930, but were unaffected by indomethacin. Thus, prolonged LTB4 inhalation can produce delayed onset airway obstruction that is stereospecific, cyclooxygenase-independent, and temporally associated with the influx of granulocytes into lung airways.