Enabling, Decagram-Scale Synthesis of Macrocyclic MCL-1 Inhibitor ABBV-467.

ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization.

Evaluation and synthesis of polar aryl- and heteroaryl spiroazetidine-piperidine acetamides as ghrelin inverse agonists.

Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile.

Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate.

The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h.

Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists.

Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism.

Sexing development and relocating gender: an organisational case study.

While gender has become increasingly mainstreamed in international development, it has lost its sharpness as an analytical tool and operational means to women's liberation. Sexuality, while it intersects with gender as a social construct, has been largely ignored within development contexts. This paper draws on findings that emerged from the gains and struggles experienced by project staff in a large international development agency engaging communities on issues related to sexual and women's rights.

White wheat flour lowers plasma cholesterol and increases cecal steroids relative to whole wheat flour, wheat bran and wheat pollard in rats.

Plasma cholesterol concentrations were significantly lower in rats fed a cholesterol-free diet containing white wheat flour than those fed the diet with whole wheat or wheat bran. Concentrations of total bile acids and neutral sterols in cecal digesta were significantly higher in rats fed wheat flour than in those fed whole wheat, wheat pollard or wheat bran. Digesta bile acids and neutral sterol pools correlated negatively with plasma cholesterol, indicating that excretion was regulating plasma concentration.

Effects of solvent extraction on the hypocholesterolaemic action of oat bran in the rat.

In adult male rats fed on a cholesterol-free synthetic diet, plasma cholesterol concentrations were lowest with oat bran, intermediate with cellulose and highest with wheat bran. Plasma triacylglycerols (TAG) were similar with wheat bran and cellulose but higher with oat bran. The concentrations and pools of caecal volatile fatty acids (VFA) were lowest with cellulose and equally higher with oat bran and wheat bran.

Effects of flow rate and insulin on triacylglycerol secretion by perfused rat liver.

In rat livers perfused with undiluted rat blood at perfusion rates of 6, 12, or 18 ml/min, hepatic O2 consumption rose with blood flow. Lipogenesis was unaffected by blood flow in control livers and was enhanced by insulin at 12 and 18 ml/min. Very-low-density lipoprotein triacylglycerol secretion also rose with increased flow and was stimulated by insulin at both 6 and 12 ml/min.

Hypocholesterolaemic effects of dietary propionate: studies in whole animals and perfused rat liver.

In adult male rats fed a non-purified diet supplemented with 5% sodium propionate, plasma cholesterol concentrations were significantly depressed. Although liver cholesterol was increased by feeding propionate, rates of hepatic cholesterol and fatty acid synthesis were unchanged. Tissue concentrations and rates of synthesis of cholesterol were also unaffected by dietary propionate in stomach, small intestine and caecum.

Failure of insulin to stimulate lipogenesis and triacylglycerol secretion in perfused livers from rats adapted to dietary fish oil.

Livers from male rats fed a standard commercial diet supplemented with 8% (w/w) marine fish or safflower oils were perfused for 70 min with undiluted blood in the presence and absence of insulin. Lipogenesis, as measured by the incorporation of 3H2O into liver and perfusate fatty acids, was inhibited by the feeding of fish oil. Net triacylglycerol secretion was also depressed by this dietary treatment.

Effects of haematocrit value and glucagon on the metabolism of perfused rat liver.

Liver from adult male rats were perfused in situ for 30 min with either undiluted, defibrinated rat blood (haematocrit value 38%) or the same blood diluted with buffer to give a haematocrit of 20%. Perfusion with diluted blood lowered the PO2 of the effluent perfusate but this was insufficient to prevent the fall in O2 consumption due to the reduction in haematocrit. Glucagon (5 X 10(-9) M) increased hepatic O2 consumption with whole blood but not with diluted blood.

Time-course of changes in plasma lipids in diabetic rats fed diets high in fish or safflower oils.

Adult male rats were maintained for 10 days on a standard chow diet or that diet supplemented with either safflower or marine fish oils, and then rendered diabetic with streptozotocin (40 mg/kg of body weight) and circulating metabolites determined over the next 3 days. Pre-diabetic concentrations of glucose and insulin did not differ between groups, and the severity of hyperglycaemia and lowering of insulin in streptozotocin-treated animals were also similar. Pre-diabetic concentrations of plasma free fatty acids and triacylglycerols were lower, and blood ketone bodies were higher in non-diabetic rats fed fish oil than in both other groups.

O2 dependence of insulin stimulation of glucose uptake by perfused rat liver: effects of carboxyhaemoglobin and haematocrit.

Livers from fed male rats were perfused in a non-recirculating system with undiluted rat blood containing 14 mM glucose. In these experiments there was a substantial uptake of glucose which was stimulated by insulin. Perfusion with blood containing carboxyhaemoglobin at a concentration of 40% of total haemoglobin lowered O2 consumption and abolished hepatic glucose uptake in control and insulin-infused livers, respectively.

Dependence on blood acetate concentration of the metabolic effects of ethanol in perfused rat liver.

In livers from fed rats perfused with recirculating blood, infusion of ethanol produced an inhibition of ketogenesis followed by substantially increased production. Perfusate lactate concentrations fell markedly following the increase in ketone body formation. In these experiments perfusate acetate rose continuously, reaching a concentration of 10 mM at 70 min, while in a control liver concentrations remained very low.

The adaptive effects of dietary fish and safflower oil on lipid and lipoprotein metabolism in perfused rat liver.

To elucidate the mechanisms underlying the plasma triacylglycerol-lowering effects of certain fish oils, livers from male rats fed either a standard commercial diet (controls) or diets supplemented with 15% (w/w) fish or safflower oils were perfused with undiluted rat blood. Rates of hepatic lipogenesis, measured by the incorporation of 3H2O into fatty acids, followed the order: control greater than safflower oil greater than fish oil. Secretion of newly synthesized fatty acids in very-low-density lipoproteins was also inhibited by the feeding of both oil-supplemented diets with the greater suppression being seen in livers from animals fed fish oil.

Metabolism of [U-14C, 2-3H] glucose in rat liver during non-recirculating perfusion: effects of insulin.

Livers from fed male rats were perfused in a non-recirculating manner with undiluted blood containing either 6 or 13 mM [U-14C,2-3H] glucose. At the lower concentration there was a small output of glucose which was unaffected by insulin whereas at the high concentration there was a substantial uptake of glucose which was significantly increased by the hormone. The rate of metabolism of [2-3H] glucose was greater than that of [U-14C] glucose in all experiments indicating an active substrate cycle between glucose:glucose 6-phosphate.

Isolation buffer calcium concentration and subsequent acute effects of insulin on metabolism of perfused rat liver.

During the surgical isolation for subsequent perfusion in situ with blood containing 1.3 mM Ca, livers from fed male rats were perfused with buffer containing 1.3 or 3.

Impaired sensitivity to insulin of rat livers perfused with blood of diminished haematocrit.

1. In livers from fed rats perfused with homologous whole blood of a haematocrit value of 37%, insulin decreased the perfusate concentrations of glucose and amino acids, production of ketone bodies (3-hydroxybutyrate + acetoacetate) and increased bile flow. 2.

Effects of dietary saponins on fecal bile acids and neutral sterols, plasma lipids and lipoprotein turnover in the pig.

Four young mature male pigs, 110 to 120 kg of body weight, were maintained on a low (0.01%) cholesterol diet. A double changeover design was used so that at any time two pigs received additionally 20 g/day of saponins as a 0.

Acute effects of ethanol on the perfused rat liver. Studies on lipid and carbohydrate metabolism, substrate cycling and perfusate amino acids.

1. Livers from fed rats were perfused in situ with whole rat blood containing glucose labelled uniformly with (14)C and specifically with (3)H at positions 2, 3 or 6. 2.

Effects of saponins on bile acids and plasma lipids in the rat.

1. The effects of feeding isolated saponins on plasma lipid concentrations and on concentrations of biliary and faecal bile acids and neutral sterols were studied in the rat. 2.