ABSTRACT
The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.
Subject(s)
Antihypertensive Agents/chemistry , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Piperidines/chemistry , Piperidines/therapeutic use , Renin/antagonists & inhibitors , Animals , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Biological Availability , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors , Dogs , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Piperidines/pharmacokinetics , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Transgenic , Renin/metabolism , Structure-Activity RelationshipABSTRACT
The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by committing the necessary resources to the development of synthetic sequences and scaffolds that were most amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.
Subject(s)
Alcohols/chemical synthesis , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/therapeutic use , Drug Design , Hypertension/drug therapy , Piperidines/chemical synthesis , Renin/antagonists & inhibitors , Alcohols/chemistry , Alcohols/therapeutic use , Animals , Antihypertensive Agents/chemistry , Molecular Structure , Piperidines/chemistry , Piperidines/therapeutic use , Rats , Renin/chemistry , Structure-Activity RelationshipABSTRACT
The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within.
Subject(s)
Protease Inhibitors/chemical synthesis , Renin/antagonists & inhibitors , Administration, Oral , Animals , Catalytic Domain , Computer Simulation , Dogs , Drug Evaluation, Preclinical , Humans , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacokinetics , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Renin/metabolism , Structure-Activity RelationshipABSTRACT
Microsomal prostaglandin E(2) synthase (mPGES-1) represents a potential target for novel analgesic and anti-inflammatory agents. High-throughput screening identified several leads of mPGES-1 inhibitors which were further optimized for potency and selectivity. A series of inhibitors bearing a biaryl imidazole scaffold exhibits excellent inhibition of PGE(2) production in enzymatic and cell-based assays. The synthesis of these molecules and their activities will be discussed.
Subject(s)
Anti-Inflammatory Agents/chemistry , Imidazoles/chemistry , Imidazoles/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Microsomes/enzymology , Animals , Anti-Inflammatory Agents/pharmacology , Cell Line , Dinoprostone/antagonists & inhibitors , Dinoprostone/biosynthesis , High-Throughput Screening Assays , Mice , Prostaglandin-E SynthasesABSTRACT
The discovery and SAR of a series of potent renin inhibitors possessing a novel biaryl scaffold are described herein. Molecular modeling revealed that the cyclopropylamide spacer present in 1 can be replaced by a simple, substituted aromatic ring such as a toluene in 2. The resulting compounds exhibit subnanomolar renin IC(50) and good oral bioavailability in rats.
Subject(s)
Bibenzyls/chemistry , Enzyme Inhibitors/chemistry , Renin/antagonists & inhibitors , Administration, Oral , Amides/chemistry , Animals , Bibenzyls/chemical synthesis , Bibenzyls/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Rats , Renin/metabolism , Structure-Activity RelationshipABSTRACT
The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.
ABSTRACT
Two different series of very potent and selective EP(3) antagonists have been reported: a novel series of ortho-substituted cinnamic acids [Belley, M., Gallant, M., Roy, B., Houde, K., Lachance, N., Labelle, M., Trimble, L., Chauret, N., Li, C., Sawyer, N., Tremblay, N., Lamontagne, S., Carrière, M.-C., Denis, D., Greig, G. M., Slipetz, D., Metters, K. M., Gordon, R., Chan, C. C., Zamboni, R. J. Bioorg. Med. Chem. Lett.2005, 15, 527] and the acylsulfonamides of ortho-(arylmethyl)cinnamates. [(a) Juteau, H., Gareau, Y., Labelle, M., Sturino, C. F., Sawyer, N., Tremblay, N., Lamontagne, S., Carrière, M.-C., Denis, D., Metters, K. M. Bioorg. Med. Chem. 2001, 9, 1977; (b) Juteau, H., Gareau, Y., Labelle, M., Lamontagne, S., Tremblay, N., Carrière, M.-C., Denis, D., Sawyer, N., Metters, K. M. Bioorg. Med. Chem. Lett.2001, 11, 747] The structural differences between the two series, along with their biological activity in vivo, in vitro, and metabolism, are analyzed. Some of those compounds, including hybrids containing the best structural features of both series, possess K(i) as low as 0.6 nM on the EP(3) receptor.
Subject(s)
Cinnamates/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Sulfonamides/pharmacology , Cinnamates/chemistry , Humans , Sulfonamides/chemistryABSTRACT
[reaction: see text] The chemical behavior of 1,2-bis-triisopropylsilanylsulfanyl alkenes 1 is relatively unexplored, and the weak sulfur-silicon bonds give rise to various transformations. Under acidic conditions (HCl) and in the presence of a Lewis acid at room temperature the bicyclic adduct 2 is obtained in good yield. The structure was confirmed by X-ray crystal analysis with R = benzyl.
ABSTRACT
A series of potent and selective inhibitors of the inducible microsomal PGE2 synthase (mPGES-1) has been developed based on the indole FLAP inhibitor MK-886. Compounds 23 and 30 inhibit mPGES-1 with potencies in the low nanomolar range and with selectivities of at least 100-fold compared to their inhibition of mPGES-2, thromboxane synthase and binding affinity to FLAP. They also block the production of PGE2 in cell based assays but with a decreased potency and more limited selectivity compared to the enzyme assays.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclooxygenase Inhibitors/chemistry , Humans , Indoles/chemistry , Microsomes/enzymology , Prostaglandin-E Synthases , Structure-Activity RelationshipABSTRACT
Johnson-type acetals derived from dimethyl tartrate give, after opening with Me(2)BBr and cuprate displacement, secondary alcohols with high diastereoselectivity (>30:1). The mechanism proposed for the induction of diastereoselectivity is downstream from the ring fission. It implies a direct participation of the Lewis acid as a source of nucleophile and the stereospecific transformation of the resulting bromo acetal through an invertive and temperature-dependent process. The acetals are prepared by reaction of the desired aldehyde with dimethyl tartrate. Removal of the auxiliary is accomplished through SmI(2) reduction or by an addition-elimination protocol using methoxide.