ABSTRACT
Penetrating head injury is a serious open cranial injury. In civilians, it is often caused by non-missile, low velocity flying objects that penetrate the skull through a weak cranial structure, forming intracranial foreign bodies. The intracranial foreign body can be displaced due to its special quality, shape, and location. In this paper, we report a rare case of right-to-left displacement of an airgun lead bullet after transorbital entry into the skull complicated by posttraumatic epilepsy, as a reminder to colleagues that intracranial metal foreign bodies maybe displaced intraoperatively. In addition, we have found that the presence of intracranial metallic foreign bodies may be a factor for the posttraumatic epilepsy, and their timely removal appears to be beneficial for epilepsy control.
ABSTRACT
As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.
Subject(s)
Drug Discovery , Imidazoles/chemistry , Imidazoles/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Dogs , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Macaca fascicularis , Mice , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.
ABSTRACT
Based on their structural similarity to previously described compound AMG 009, indole-phenyl acetic acids were proposed to be potent dual inhibitors of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2) and prostanoid D receptor (DP or DP1). This series was equipotent to AMG 009 in binding assays against both receptors but exhibited decreased serum shift. We discovered early in the optimization of these indole-phenylacetic acid compounds that they demonstrated CYP3A4 time-dependent inhibition (TDI). Hypothesizing that the source of TDI was the indole core we modified the 1,2,3-substitution to eventually afford a highly potent modulator of CRTH2 and DP which did not exhibit TDI.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Phenylacetates/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indoles/chemistry , Molecular Structure , Phenylacetates/chemistry , Structure-Activity Relationship , Time FactorsABSTRACT
We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties.
Subject(s)
Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Receptors, G-Protein-Coupled/agonists , Aniline Compounds/chemical synthesis , Animals , Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Humans , Mice , Models, Molecular , Receptors, G-Protein-Coupled/chemistry , Structure-Activity RelationshipABSTRACT
GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.
ABSTRACT
Our first generation CRTH2 and DP dual antagonists, represented by AMG 009, are more potent toward the CRTH2 receptor than to the DP receptor. Here we report our efforts in the discovery of CRTH2 and DP dual antagonists with more balanced potencies to both receptors, such as compound 15.
Subject(s)
Drug Design , Phenylacetates/chemical synthesis , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , HEK293 Cells , Humans , Inhibitory Concentration 50 , Molecular Structure , Phenylacetates/chemistry , Phenylacetates/pharmacology , Protein Binding/drug effectsABSTRACT
The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay. Compound 25 was identified as having the optimal balance of CXCR3 activity and pharmacokinetic properties across multiple pre-clinical species, which are reported herein.
Subject(s)
Quinazolines/chemical synthesis , Quinazolinones/chemical synthesis , Receptors, CXCR3/antagonists & inhibitors , Animals , Bleomycin/toxicity , Chromosome Aberrations , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Dogs , Dose-Response Relationship, Drug , Drug Design , Humans , Inflammation , Inhibitory Concentration 50 , Leukocytes/drug effects , Macaca fascicularis , Mice , Models, Chemical , Quinazolines/pharmacology , Quinazolinones/pharmacology , Time FactorsABSTRACT
A series of benzothiazinone and benzooxazinone derivatives were discovered as SGLT2 inhibitors. The optimization led to the discovery of compounds 31 and 32, which exhibited similar potency and better SGLT1 selectivity compared to dapagliflozin. These compounds may provide novel promising scaffolds, which are different from phlorizin-based SGLT2 inhibitors.
Subject(s)
Benzoxazines/chemistry , Sodium-Glucose Transporter 2 Inhibitors , Triazoles/chemistry , Animals , Benzoxazines/chemical synthesis , Benzoxazines/pharmacology , Drug Evaluation, Preclinical , Humans , Mice , Rats , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 1/metabolism , Sodium-Glucose Transporter 2/metabolism , Thiazines/chemical synthesis , Thiazines/chemistry , Thiazines/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacologyABSTRACT
Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2. These efforts led to the discovery of AMG 853 (2-(4-(4-(tert-butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenyl sulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid), which is being evaluated in human clinical trials for asthma.
ABSTRACT
The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties. We will also discuss the efficacy of the lead compound 34 in a mouse model of cellular recruitment induced by bleomycin.
Subject(s)
Anti-Inflammatory Agents/chemistry , Pyrimidinones/chemistry , Quinazolinones/chemistry , Receptors, CXCR3/antagonists & inhibitors , Sulfones/chemistry , Acetamides/pharmacology , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Cell Movement , Dogs , Haplorhini , Humans , Mice , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Quinazolinones/chemical synthesis , Quinazolinones/pharmacokinetics , Rats , Receptors, CXCR3/metabolism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
A series of imidazole derivatives have been designed and optimized for CXCR3 antagonism, pharmacokinetic properties, and reduced formation of glutathione conjugates. Our efforts led to the discovery of potent CXCR3 antagonists with good pharmacokinetic properties. These compounds are useful tools for in vivo studies of CXCR3 function.
Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Animals , Chromatography, High Pressure Liquid , Drug Design , Humans , Imidazoles/pharmacokinetics , Mice , Mice, Knockout , Rats , Receptors, CXCR3/genetics , Receptors, CXCR3/physiology , Structure-Activity RelationshipABSTRACT
A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo.
Subject(s)
Heterocyclic Compounds/pharmacology , Quinazolinones/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Animals , Chromatography, High Pressure Liquid , Humans , Quinazolinones/pharmacokinetics , Rats , StereoisomerismABSTRACT
A series of quinazolinone-derived inhibitors of the CXCR3 receptor have been synthesized and their affinity for the receptor evaluated. Compounds were evaluated in a (125)I-IP10 displacement assay and in in vitro cell migration assays to IP10, ITAC, and MIG using human peripheral blood mononuclear cells.
Subject(s)
Cell Movement/drug effects , Quinazolinones/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Animals , Cell Culture Techniques , Cell Movement/physiology , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Iodine Radioisotopes , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Mice , Models, Chemical , Oligopeptides/metabolism , Quinazolinones/chemical synthesis , Radioligand Assay , Receptors, CXCR3 , Receptors, Cytokine/metabolism , Structure-Activity RelationshipABSTRACT
OBJECTIVE: To evaluate the quality of life (QOL) of patients with hypertension. METHODS: Totally 319 patients with hypertension were investigated for their QOL in comparison with 319 healthy controls using the World Health Organization Quality of Life assessment instrument (WHOQOL-100). RESULTS: The scores of physical functions, psychological condition, independent ability, social relation, living environment, and personal faith and the total score of QOL-100 were significantly lower in the hypertensive patients than in the normal subjects (P<0.01). After adjusting the confounding factors of other diseases, the scores of all the items with the exception of personal faith and the total score of QOL-100 were all lower in the patients than in the controls (P<0.01). Hostelling T2 test and multivariate analysis of variance showed significant differences in the QOL between the hypertensive patients and the controls in the 6 domains synthesized (P<0.01), further demonstrating lowered QOL of hypertensive patients in comparison with the healthy population. CONCLUSION: Improvement of the hypertensive patients' QOL in addition to effective blood pressure control is a basic target in clinical therapy of hypertension.
