ABSTRACT
A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.
ABSTRACT
New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay.
Subject(s)
Isoquinolines/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Quinazolines/chemistry , Receptor, Adenosine A2A/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/pharmacokinetics , Animals , Binding Sites , Drug Design , Half-Life , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Structure, Tertiary , Quinazolines/chemical synthesis , Quinazolines/pharmacokinetics , Rats , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
Diacylglycerol acyltransferase 1 (DGAT1) presents itself as a potential therapeutic target for obesity and diabetes for its important role in triglyceride biosynthesis. Herein we report the rational design of a novel class of DGAT1 inhibitors featuring a benzomorpholine core (23n). SAR exploration yielded compounds with good potency and selectivity as well as reasonable physical and pharmacokinetic properties. This class of DGAT1 inhibitors was tested in rodent models to evaluate DGAT1 inhibition as a novel approach for the treatment of metabolic diseases. Compound 23n conferred weight loss and a reduction in liver triglycerides when dosed chronically in mice with diet-induced obesity and depleted serum triglycerides following a lipid challenge.
ABSTRACT
A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats.
Subject(s)
Amides/chemistry , Azoles/pharmacology , Drug Discovery , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Azoles/chemical synthesis , Azoles/chemistry , Dose-Response Relationship, Drug , Intracellular Signaling Peptides and Proteins/metabolism , Molecular Conformation , Permeability/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure-activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
Subject(s)
Carboxylic Acids/pharmacology , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Quinolones/pharmacology , Animals , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Diacylglycerol O-Acyltransferase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Mice , Models, Molecular , Molecular Structure , Quinolones/chemical synthesis , Quinolones/chemistry , Structure-Activity RelationshipABSTRACT
Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.
Subject(s)
Amides/chemistry , Drug Design , Isoxazoles/chemistry , Quinazolinones/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Animals , Dogs , Half-Life , Haplorhini , Humans , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Quinazolinones/chemical synthesis , Quinazolinones/pharmacokinetics , Rats , Rats, Wistar , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Oxazoles/chemistry , Proline/analogs & derivatives , Quinolines/chemical synthesis , Administration, Oral , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Evaluation, Preclinical , Half-Life , Inhalation , Oxazoles/chemical synthesis , Oxazoles/pharmacokinetics , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacokinetics , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9µMh.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacology , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Cytochrome P-450 Enzyme System/metabolism , Guinea Pigs , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Rats , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.
Subject(s)
Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/therapeutic use , Obesity/drug therapy , Animals , Histamine H3 Antagonists/metabolism , Histamine H3 Antagonists/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Rats , Receptors, Histamine H3/metabolismABSTRACT
Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.
Subject(s)
Anilides/chemistry , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Lactams/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Anilides/chemical synthesis , Anilides/metabolism , Binding, Competitive , Drug Evaluation, Preclinical , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Lactams/chemical synthesis , Lactams/metabolism , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Serine-Threonine Kinases/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.
Subject(s)
Amides/pharmacology , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Animals , Diacylglycerol O-Acyltransferase/metabolism , Enzyme Inhibitors/chemistry , Humans , Mice , Structure-Activity RelationshipABSTRACT
In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Azepines/chemical synthesis , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Animals , Azepines/chemistry , Azepines/pharmacology , ERG1 Potassium Channel , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Subject(s)
Antifungal Agents/chemistry , Enzyme Inhibitors/chemistry , Glucosyltransferases/antagonists & inhibitors , Pyridazines/chemistry , Sulfonamides/chemistry , Animals , Antifungal Agents/pharmacokinetics , Antifungal Agents/therapeutic use , Candida/drug effects , Candidiasis/drug therapy , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Glucosyltransferases/metabolism , Half-Life , Mice , Microbial Sensitivity Tests , Pyridazines/pharmacokinetics , Pyridazines/therapeutic use , Rats , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Subject(s)
Antifungal Agents/chemistry , Enzyme Inhibitors/chemistry , Glucosyltransferases/antagonists & inhibitors , Lead/chemistry , Piperazines/chemistry , Pyridazines/chemistry , Sulfonylurea Compounds/chemistry , Animals , Antifungal Agents/pharmacology , Candida/drug effects , Cell Line , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Piperazine , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Sulfonylurea Compounds/pharmacologyABSTRACT
The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.
Subject(s)
Receptors, Glucocorticoid/drug effects , Steroids/chemistry , Sulfides/chemistry , Humans , Hydrocortisone , Pyrazoles/chemistry , Structure-Activity Relationship , Sulfides/pharmacology , Transcriptional Activation/drug effectsABSTRACT
A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.
Subject(s)
Histamine H3 Antagonists/pharmacokinetics , Thiadiazoles/pharmacology , Administration, Oral , Animals , Ketones , Obesity/drug therapy , Rats , Structure-Activity Relationship , Thiadiazoles/pharmacokineticsABSTRACT
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Oxazoles/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemical synthesis , Quinolines/chemical synthesis , Animals , Anti-Inflammatory Agents/pharmacology , Cyclic N-Oxides/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Discovery , Humans , Models, Molecular , Oxazoles/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H(3) antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H(3) antagonist activity in both ex vivo and in vivo assays.
Subject(s)
Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacology , Receptors, Histamine H3/metabolism , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Mice , Rats , Structure-Activity RelationshipABSTRACT
Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.