RESUMO
Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.
Assuntos
Dibenzoxazepinas/síntese química , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/síntese química , Fígado/enzimologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Animais , Ciclização , Dibenzoxazepinas/farmacocinética , Dibenzoxazepinas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Camundongos , Modelos Animais , Estrutura Molecular , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologiaRESUMO
Monkey studies were conducted for the preclinical safety assessment of SCH 412499, an adenovirus encoding p21, administered by subconjunctival injection prior to trabeculectomy for postoperative maintenance of the surgical opening. Biodistribution of SCH 412499 was minimal and there was no systemic toxicity. Findings included swollen, partially closed or shut eye(s) and transient congestion in the conjunctiva. A mononuclear cell infiltrate was present in the conjunctiva, choroid and other ocular tissues, but completely or partially resolved over time. Electroretinograms and visual evoked potentials revealed no adverse findings. Thus, the findings are not expected to preclude the clinical investigation of SCH 412499.
Assuntos
Adenoviridae/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Terapia Genética , Implantes para Drenagem de Glaucoma , Anestesia , Animais , Pressão Sanguínea/fisiologia , Túnica Conjuntiva , Conjuntivite/patologia , Eletrorretinografia , Ensaio de Imunoadsorção Enzimática , Potenciais Evocados Visuais/fisiologia , Olho/patologia , Feminino , Frequência Cardíaca/fisiologia , Injeções , Macaca fascicularis , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Distribuição Tecidual , Malha Trabecular , CicatrizaçãoRESUMO
Mononuclear cell infiltrate (MCI) in the uvea was observed in naïve, untreated (control group) cynomolgus monkeys in approximately 25% of drug safety evaluation studies. The total incidence of MCI in the choroid and the ciliary body was 29% of 342 males and 25% of 306 female monkeys. In the studies in which MCI was present in the ciliary body or choroid, the incidence was as high as 75%. There were no other ocular histopathologic findings in these monkeys. All monkeys were clinically healthy and the eyes were not remarkable when examined ophthalmoscopically.
Assuntos
Leucócitos Mononucleares/patologia , Doenças dos Macacos/patologia , Úvea/patologia , Uveíte/veterinária , Animais , Corioide/patologia , Corpo Ciliar/patologia , Feminino , Iris/patologia , Macaca fascicularis , Masculino , Testes de Toxicidade , Uveíte/patologiaRESUMO
Today the countries of the English-speaking Carribean are at a crossroads. While the old problem of malnutrition in children has declined sharply, a large proportion of adults suffer from obesity. Estimates, according to Caribbean experts, are that 30 per cent of the population above 35 years of age are suffering from high blood pressure and 10-12 per cent from diabetes. The report "Health of the Americas" by the Pan American Health Organization shows that the countries are threatened with a massive epidemic of diabetes, hypertension, heart attack, stroke and cancer among adults, as these diseases are among the first five principal causes of deaths
