ABSTRACT
The optimization for selectivity and central receptor occupancy for a series of spirocyclic azetidine-piperidine inverse agonists of the ghrelin receptor is described. Decreased mAChR muscarinic M2 binding was achieved by use of a chiral indane in place of a substituted benzylic group. Compounds with desirable balance of human in vitro clearance and ex vivo central receptor occupancy were discovered by incorporation of heterocycles. Specifically, heteroaryl rings with nitrogen(s) vicinal to the indane linkage provided the most attractive overall properties.
Subject(s)
Central Nervous System/drug effects , Receptors, Ghrelin/antagonists & inhibitors , Amino Acid Sequence , Animals , Binding Sites , Drug Inverse Agonism , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Indans/chemistry , Indans/pharmacology , Inhibitory Concentration 50 , Isomerism , Molecular Structure , Protein Binding/drug effects , Rats , Structure-Activity RelationshipABSTRACT
The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.
Subject(s)
Drug Discovery , Heptanoic Acids/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Hypercholesterolemia/drug therapy , Imidazoles/chemical synthesis , Liver/drug effects , Animals , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Hepatocytes/drug effects , Heptanoic Acids/chemistry , Heptanoic Acids/pharmacokinetics , Heptanoic Acids/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Tissue DistributionABSTRACT
This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Animals , Cricetinae , Dose-Response Relationship, Drug , Drug Design , Fluorobenzenes , Hyperlipidemias/drug therapy , Liver/drug effects , Models, Molecular , Molecular Structure , Pyrimidines , Rosuvastatin Calcium , Structure-Activity Relationship , SulfonamidesABSTRACT
Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.
Subject(s)
Benzofurans/chemistry , Chemistry, Pharmaceutical/methods , Indoles/chemistry , PPAR delta/agonists , Thiophenes/chemistry , Animals , Benzofurans/chemical synthesis , Drug Design , Drug Evaluation, Preclinical , Humans , Indoles/chemical synthesis , Inhibitory Concentration 50 , Ligands , Models, Chemical , Structure-Activity Relationship , Thiazoles/chemistry , Thiophenes/chemical synthesisABSTRACT
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Renin/antagonists & inhibitors , Crystallography, X-Ray , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Models, Molecular , Molecular Structure , Piperazines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
[structure: see text] Novel 6-substituted lavendamycins have been synthesized for the first time. The key step in these syntheses is a Pictet-Spengler condensation (Scheme 1). Efficient methods for the synthesis of each compound, including a novel reaction for the facile introduction of alkylamino groups at the C-6 position of the lavendamycin system, are discussed. Possible mechanisms for these reactions are also presented.
