ABSTRACT
Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.
Subject(s)
Drug Inverse Agonism , Receptors, Ghrelin/agonists , Receptors, Ghrelin/antagonists & inhibitors , Urea/analogs & derivatives , Urea/pharmacology , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Receptors, Ghrelin/metabolism , Structure-Activity Relationship , Urea/chemistryABSTRACT
At AstraZeneca a focus on hypothesis-driven design and the formation of drug design teams has placed a greater emphasis on collaboration in the drug discovery process. We have created a novel software tool based on the principles of wikis and social networks to facilitate collaborative working, visual planning and incorporation of predictive science to improve design capability. Monitoring the design and make process via the tool enabled the identification of bottlenecks and delays. Solutions to these problems were implemented, reducing the time taken from the initial idea stage to the generation of the synthesised compound by more than 50%.
Subject(s)
Drug Design , Internet , SoftwareABSTRACT
Inhibition of 11ß-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11ß-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Niacinamide/analogs & derivatives , Piperidines/pharmacology , Piperidines/pharmacokinetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Biological Availability , Dogs , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/metabolism , Humans , Inhibitory Concentration 50 , Male , Mice , Models, Molecular , Niacinamide/administration & dosage , Niacinamide/metabolism , Niacinamide/pharmacokinetics , Niacinamide/pharmacology , Piperidines/administration & dosage , Piperidines/metabolism , Protein Conformation , Rats , Substrate SpecificityABSTRACT
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Oxadiazoles/chemical synthesis , Animals , Diabetes Mellitus/drug therapy , Diacylglycerol O-Acyltransferase/metabolism , Dogs , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Half-Life , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Ligands , Mice , Obesity/drug therapy , Oxadiazoles/pharmacokinetics , Quantitative Structure-Activity Relationship , RatsABSTRACT
An imidazole series of cyclin-dependent kinase (CDK) inhibitors has been developed. Protein inhibitor structure determination has provided an understanding of the emerging structure activity trends for the imidazole series. The introduction of a methyl sulfone at the aniline terminus led to a more orally bioavailable CDK inhibitor that was progressed into clinical development.
Subject(s)
Cyclin-Dependent Kinases/antagonists & inhibitors , Imidazoles/chemistry , Aniline Compounds/chemistry , Animals , Cell Cycle Proteins/chemistry , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Checkpoint kinase-1 (Chk1, CHEK1) is a Ser/Thr protein kinase that mediates the cellular response to DNA-damage. A novel class of 2-ureido thiophene carboxamide urea (TCU) Chk1 inhibitors is described. Inhibitors in this chemotype were optimized for cellular potency and selectivity over Cdk1.
Subject(s)
Chemistry, Pharmaceutical/methods , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinases/chemistry , Amides/chemistry , Apoptosis , Carbon/chemistry , Cell Cycle , Checkpoint Kinase 1 , DNA Damage , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Phenyl Ethers/chemistry , Thiophenes/chemistry , Urea/chemistryABSTRACT
The synthesis and directed dihydroxylation of a range of cyclic alkenes was investigated. Both homoallylic alcohols and homoallylic trihaloacetamides were found to be efficient directing groups, giving rise to good to excellent levels of remote asymmetric induction with OsO4-TMEDA. Interestingly, in all cases examined, trifluoroacetamides were found to be superior to trichloroacetamides as directing groups and an argument is presented which rationalises this observation.
ABSTRACT
The oxidation of a range of cyclic allylic alcohols and amides with OsO4/TMEDA is presented. Under these conditions, hydrogen bonding control leads to the (contrasteric) formation of the syn isomer in almost every example that was examined. Evidence for the bidentate binding of TMEDA to OsO4 is presented and a plausible mechanism described.
