ABSTRACT
Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure, and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP. Previously, we have reported the crystal structure of NEP bound with LBQ657, whereby we noted the presence of a subsite in S1' that has not been explored before. We were also intrigued by the zinc coordination made by one of the carboxylic acids of LBQ657, leading us to explore alternative linkers to efficiently engage zinc for NEP inhibition. Structure-guided design culminated in the synthesis of selective, orally bioavailable, and subnanomolar inhibitors of NEP. A 17-fold boost in biochemical potency was observed upon addition of a chlorine atom that occupied the newly found subsite in S1'. We report herein the discovery and preclinical profiling of compound 13, which paved the path to our clinical candidate.
ABSTRACT
Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Diet, High-Fat , Enzyme Inhibitors/pharmacology , Obesity/physiopathology , Triglycerides/blood , Weight Gain/drug effects , Administration, Oral , Adolescent , Adult , Animals , Dogs , Double-Blind Method , Drug Discovery , Enzyme Inhibitors/administration & dosage , Female , Humans , Male , Middle Aged , Placebos , Postprandial Period , Rats , Rats, Sprague-Dawley , Young AdultABSTRACT
High DGAT1 expression levels in the small intestine highlight the critical role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented.
ABSTRACT
A series of 1-alkyl-3-phenylthiourea analogues were prepared and evaluated as HDL- and Apo A-I-elevating and triglyceride-lowering agents. Several derivatives were superior to gemfibrozil. The optimal analogue (HDL376) was shown to raise HDL cholesterol in the rat, hamster, dog, and monkey models.
Subject(s)
Gemfibrozil/pharmacology , Lipoproteins, HDL/metabolism , Phenylthiourea/chemical synthesis , Phenylthiourea/pharmacology , Administration, Oral , Animals , Centrifugation, Density Gradient , Cholesterol, HDL/metabolism , Chromatography, High Pressure Liquid , Cricetinae , Dogs , Drug Evaluation, Preclinical , Haplorhini , Lipids/chemistry , Male , Models, Chemical , Phenylthiourea/administration & dosage , Rats , Rats, Sprague-Dawley , Time Factors , Triglycerides/metabolismABSTRACT
High-throughput screening identified 5 as a weak inhibitor of 11beta-HSD1. Optimization of the structure led to a series of perhydroquinolylbenzamides, some with low nanomolar inhibitory potency. A tertiary benzamide is required for biological activity and substitution of the terminal benzamide with either electron-donating or -withdrawing groups is tolerated. The majority of the compounds show selectivity of >20 to >700-fold over 11beta-HSD2. Analogues which showed >50% inhibition of 11beta-HSD1 at 1 muM in an cellular assay were screened in an ADX mouse model. A maximal response of >70% reduction of liver corticosterone levels was observed for three compounds; 9m, 25 and 49.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/chemical synthesis , Hydroquinones/chemical synthesis , Adrenalectomy , Animals , Benzamides/chemistry , Benzamides/pharmacology , Cells, Cultured , Corticosterone/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Hydroquinones/chemistry , Hydroquinones/pharmacology , Liver/drug effects , Liver/metabolism , Male , Mice , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 1-hydroxyalkyl-3-phenylthiourea analogs were prepared and evaluated as HDL-and Apo A-I-elevating agents. Derivatives 5h, 7j, 7n, and 7o were found to be as effective or superior to gemfibrozil.
Subject(s)
Lipoproteins, HDL/drug effects , Phenylthiourea/analogs & derivatives , Phenylthiourea/pharmacology , Animals , Apolipoprotein A-I/blood , Apolipoprotein A-I/drug effects , Cholesterol/administration & dosage , Cholesterol/blood , Humans , Lipids/blood , Lipoproteins, HDL/blood , Male , Phenylthiourea/chemical synthesis , Rats , Structure-Activity Relationship , Weight Gain/drug effectsABSTRACT
A series of gemfibrozil analogues with a thiourea moiety embedded in the side chain was prepared and evaluated as HDL-elevating agents. Derivatives 8b, 9b, 9c, and 9d were found to be approximately as effective as gemfibrozil (1) for HDL cholesterol elevation.
