ABSTRACT
A hit to lead process to identify reversible, orally available ADP receptor (P2Y12) antagonists lead compounds is described. High throughput screening afforded 1. Optimization of 1, using parallel synthesis methods, a methyl scan to identify promising regions for optimization, and exploratory SAR on these regions, provided 22 and 23. Compound 23 is an orally available, competitive reversible antagonist (KBâ¯=â¯94â¯nM for inhibition of ADP-induced platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes and is orally absorbed. Although plasma level after oral dosing of 22 and 23 to rats is low, reasonable levels were achieved to merit extensive lead optimization of this structural class.
Subject(s)
Fluorenes/pharmacology , Receptors, Purinergic P2Y12/metabolism , Administration, Oral , Animals , Dogs , Dose-Response Relationship, Drug , Fluorenes/administration & dosage , Fluorenes/chemistry , High-Throughput Screening Assays , Humans , Microsomes, Liver/metabolism , Molecular Structure , Platelet Aggregation/drug effects , Rats , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of a series of aryl diamines as inhibitors of LTA(4)-h inhibitors are described. The optimization which led to the identification of the optimal para-substitution on the diphenyl ether moiety and diamine spacer is discussed. The resulting compounds such as 3l have excellent enzyme and cellular potency as well as desirable pharmacokinetic properties.
Subject(s)
Chemistry, Pharmaceutical/methods , Diamines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Epoxide Hydrolases/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents/pharmacology , Biological Availability , Diamines/chemistry , Dogs , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , RatsABSTRACT
The synthesis and biological evaluation of a series of N-alkyl glycine amide analogs as LTA(4)-h inhibitors and the importance of the introduction of a benzoic acid group to the potency and pharmacokinetic parameters of our analogs are described. The lead compound in the series, 4q, has excellent potency and oral bioavailability.
Subject(s)
Amides/chemistry , Enzyme Inhibitors/pharmacokinetics , Epoxide Hydrolases/antagonists & inhibitors , Glycine/chemistry , Administration, Oral , Amines/chemistry , Anti-Inflammatory Agents/pharmacology , Benzoic Acid/chemistry , Biological Availability , Chemistry, Pharmaceutical , Drug Design , Ethers , Inhibitory Concentration 50 , Models, ChemicalABSTRACT
A new series of 1-(1,3-benzodioxol-5-ylmethyl)-3-[4-(1H-Imidazol-1-yl)phenoxy]-piperidine analogs were designed and identified as potent and selective inhibitors of NO formation based both on the crystal structure of a murine iNOS Delta114 monomer domain/ inhibitor complex and inhibition of the NO formation in human A172 cell assays. Compound 12S showed high potency and high iNOS selectivity versus nNOS and eNOS.
Subject(s)
Chemistry, Pharmaceutical/methods , Imidazoles/chemical synthesis , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide/antagonists & inhibitors , Piperidines/chemistry , Animals , Cell Line, Tumor , Dimerization , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Imidazoles/pharmacology , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Conformation , Nitric Oxide Synthase Type I/antagonists & inhibitors , Nitric Oxide Synthase Type III/antagonists & inhibitors , Piperidines/chemical synthesis , Piperidines/pharmacologyABSTRACT
By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzodioxoles/chemical synthesis , Imidazoles/chemical synthesis , Nitric Oxide Synthase Type II/metabolism , Pyrimidines/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/therapy , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Cell Line , Chlorocebus aethiops , Crystallography, X-Ray , Dimerization , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Models, Molecular , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Inbred LewABSTRACT
The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, 1, with an IC(50) of 840 nM against the CCR5 receptor was identified using high-throughput screening. Optimization efforts led to the discovery of a novel piperidine series of CCR5 antagonists. In particular, the 4-hydroxypiperidine derivative, 6k, had improved potency against CCR5, and was a starting point for further optimization. SAR elaboration using parallel synthesis led to the identification of 10h, a potent CCR5 antagonist with an IC(50) of 11 nM.
Subject(s)
CCR5 Receptor Antagonists , Chemistry, Pharmaceutical/methods , Piperidines/chemistry , Animals , Cell Line , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Molecular Structure , Piperidines/chemical synthesis , Piperidines/pharmacology , Rats , Structure-Activity Relationship , Time Factors , TransfectionABSTRACT
High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.
