ABSTRACT
Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
Subject(s)
Arginine/analogs & derivatives , Flavones/chemistry , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Animals , Arginine/chemical synthesis , Arginine/chemistry , Arginine/pharmacology , Brain/metabolism , Caco-2 Cells , Cell Membrane Permeability , Feeding Behavior/drug effects , Flavones/chemical synthesis , Flavones/pharmacology , HEK293 Cells , Humans , Male , Membranes, Artificial , Mice, Knockout , Microsomes, Liver/metabolism , Mutation , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/genetics , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/pharmacokinetics , Serotonin 5-HT2 Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Design , Pyrroles/chemistry , Pyrroles/pharmacology , Acetamides/chemical synthesis , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Catalytic Domain , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Glucose Tolerance Test , Humans , Male , Mice , Models, Molecular , Pyrroles/chemical synthesis , Substrate SpecificityABSTRACT
A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Isoquinolines/chemistry , Pyrroles/chemistry , Pyrroles/chemical synthesis , Receptor, Serotonin, 5-HT2C/chemistry , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Animals , Half-Life , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Humans , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Male , Pyrroles/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/chemistry , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/chemistry , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/chemistry , Serotonin 5-HT2 Receptor Agonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Previously, potent factor Xa inhibitors were described based on the 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one bicyclic core and a 4-methoxyphenyl P1 moiety. This manuscript describes 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one and related bicyclic cores with the 3-aminobenzisoxazole P1 moiety. Many of these compounds are potent, selective, and efficacious inhibitors of coagulation factor Xa.
Subject(s)
Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Anticoagulants/pharmacology , Humans , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Substrate Specificity , Thromboembolism/drug therapyABSTRACT
Previously, potent factor Xa inhibitors were described based on a pyrazole core. Modifications of the pyrazole core have provided additional novel, highly potent factor Xa inhibitors. This manuscript will describe the synthesis and biological activity of factor Xa inhibitors containing the 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one and related bicyclic cores. Many of these compounds are potent, selective, and orally bioavailable inhibitors of coagulation factor Xa.
Subject(s)
Antithrombin III/chemical synthesis , Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Pyrimidinones/chemical synthesis , Administration, Oral , Animals , Antithrombin III/pharmacology , Biological Availability , Crystallography, X-Ray , Dogs , Fibrinolytic Agents/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrimidinones/pharmacology , Thrombosis/drug therapy , Thrombosis/prevention & controlABSTRACT
We have previously reported on a series of aminobenzisoxazoles as potent, selective, and orally bioavailable factor Xa inhibitors, which culminated in the discovery of razaxaban. Herein, we describe another approach to improve factor Xa inhibitory potency and pharmacokinetic profile by incorporating basic and water soluble functionalities on the terminal ring of the P4 biaryl group found in our earlier Xa inhibitors. This approach resulted in a series of potent, selective, and orally bioavailable factor Xa inhibitors.
Subject(s)
Benzoxazoles/pharmacology , Factor Xa Inhibitors , Serine Proteinase Inhibitors/pharmacology , Administration, Oral , Benzoxazoles/administration & dosage , Benzoxazoles/chemistry , Benzoxazoles/pharmacokinetics , Biological Availability , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K(i) of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.
