ABSTRACT
Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.
Subject(s)
Antihypertensive Agents/pharmacology , Enzyme Inhibitors/pharmacology , Phenyl Ethers/pharmacology , Renin/antagonists & inhibitors , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/chemistry , Biological Availability , Crystallography, X-Ray , Cytochrome P-450 CYP3A/blood , Cytochrome P-450 CYP3A Inhibitors , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hypertension/drug therapy , Models, Molecular , Molecular Conformation , Phenyl Ethers/chemical synthesis , Phenyl Ethers/chemistry , Rats , Rats, Transgenic , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/isolation & purification , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
ABSTRACT
Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Drug Design , Urea/administration & dosage , Urea/pharmacokinetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Binding Sites/physiology , Biological Availability , CHO Cells , Cricetinae , Cricetulus , Humans , Macaca fascicularis , Mice , Rats , Structure-Activity Relationship , Urea/analogs & derivativesABSTRACT
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
Subject(s)
Amines/chemistry , Carbamates/chemistry , Enzyme Inhibitors/chemistry , Piperidines/chemistry , Renin/antagonists & inhibitors , Administration, Oral , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Binding Sites , Blood Pressure/drug effects , Carbamates/chemical synthesis , Carbamates/pharmacokinetics , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Haplorhini , Humans , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats , Rats, Transgenic , Renin/blood , Renin/metabolism , Structure-Activity RelationshipABSTRACT
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
Subject(s)
Antihypertensive Agents/chemistry , Methylamines/chemistry , Renin/antagonists & inhibitors , Administration, Oral , Amino Acid Sequence , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Blood Pressure , Computer Simulation , Crystallography, X-Ray , Drug Design , Humans , Methylamines/chemical synthesis , Methylamines/pharmacokinetics , Rats , Rats, Transgenic , Renin/metabolism , Structure-Activity RelationshipABSTRACT
A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce >400 kg of cyclized product.
Subject(s)
Antiviral Agents/chemical synthesis , Carbamates/chemical synthesis , Hepacivirus/enzymology , Macrocyclic Compounds/chemical synthesis , Protease Inhibitors/chemical synthesis , Quinolines/chemical synthesis , Thiazoles/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Chromatography, High Pressure Liquid , Cyclization , Hepacivirus/drug effects , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Molecular Structure , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
The Boehringer-Ingelheim phosphinoimidazoline (BIPI) ligands were applied to the formation of chiral quaternary centers in the asymmetric Heck reaction. Several different substrates were examined in detail, using more than 70 members of this new ligand class. Hammett relationships were determined through systematic variation of the ligand electronics. All substrates showed essentially the same Hammett behavior, where enantioselectivity increased as the ligands were made more electron-deficient. Ligand optimization has led to catalysts which give the highest enantioselectivities reported to date for these difficult systems.
