ABSTRACT
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
Subject(s)
2-Aminopurine/chemistry , 2-Aminopurine/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Purines/chemistry , Reperfusion Injury/enzymology , Animals , Catalytic Domain , Dogs , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haplorhini , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Purines/pharmacology , Rats , Reperfusion Injury/drug therapy , Structure-Activity RelationshipABSTRACT
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.
Subject(s)
Cyclohexanols/chemistry , Cyclohexanols/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , MAP Kinase Kinase 4/antagonists & inhibitors , Purines/chemistry , Purines/pharmacology , Administration, Oral , Animals , Catalytic Domain , Cyclohexanols/administration & dosage , Dogs , Enzyme Activation/drug effects , Enzyme Inhibitors/administration & dosage , Haplorhini , Idiopathic Pulmonary Fibrosis/drug therapy , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Purines/administration & dosage , Rats , Structure-Activity RelationshipABSTRACT
OBJECTIVE: The purpose of this study was to compare patient characteristics and diagnoses in a comprehensive Women's Health Care Clinic between gynecologists and internal medicine physicians. STUDY DESIGN: This retrospective cohort study evaluated International Classification of Diseases, 9th Revision, codes that were recorded between January 1, 2001, and January 4, 2004, at the Women's Health Care Clinic. We compared demographics and prevalence of diagnosis codes for patients who were seen by obstetricians/gynecologists and internal medicine physicians and compared these data with national survey statistics. A sampling of charts was reviewed for coding verification. RESULTS: We analyzed 13,462 visits at the Women's Health Care Clinic. Patients who were seen by internists were older, had greater racial diversity, and had more gender-nonspecific medical disorders (hypertension, depression). Gynecologists saw more specific women's health problems (P < .05). The diagnoses of menstrual disorders, menopause, pelvic pain, and abnormal cytologic findings within the Women's Health Care Clinic follow closely with the national ambulatory survey data. CONCLUSION: Within this multispecialty Women's Health Care Clinic, internal medicine physicians are practicing primary care and obstetricians/gynecologists are providing specialty care.
Subject(s)
Ambulatory Care Facilities , Gynecology/methods , Internal Medicine/methods , Primary Health Care/methods , Women's Health Services , Adolescent , Adult , Aged , Ambulatory Care Facilities/statistics & numerical data , Cohort Studies , Female , Humans , International Classification of Diseases/statistics & numerical data , Middle Aged , Obstetrics/methods , Retrospective Studies , Women's Health Services/statistics & numerical dataABSTRACT
Lewis acid-mediated nucleophilic substitution reactions of substituted tetrahydropyran acetates reveal that the conformational preferences of six-membered-ring cations depend significantly upon the electronic nature of the substituent. Nucleophilic substitutions of C-3 and C-4 alkyl-substituted tetrahydropyran acetates proceeded via pseudoequatorially substituted oxocarbenium ions, as would be expected by consideration of steric effects. Substitutions of C-3 and C-4 alkoxy-substituted tetrahydropyran acetates, however, proceeded via pseudoaxially oriented oxocarbenium ions. The unusual selectivities controlled by the alkoxy groups were demonstrated for a range of other heteroatom substituents, including nitrogen, fluorine, chlorine, and bromine. It is believed that the pseudoaxial conformation is preferred in the ground state of the cation because of an electrostatic attraction between the cationic carbon center of the oxocarbenium ion and the heteroatom substituent. This analysis is supported by the observation that selectivity diminishes down the halogen series, which is inconsistent with electron donation as might be expected during anchimeric assistance. The C-2 heteroatom-substituted systems gave moderately high 1,2-cis selectivity, while small alkyl substituents showed no selectivity. Only in the case of the tert-butyl group at C-2 was high 1,2-trans selectivity observed. These studies reinforce the idea that ground-state conformational effects need to be considered along with steric approach considerations.