Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors.
新型吡唑并嘧啶类药物作为强效和口服生物可利用的变构 HIV-1 整合酶抑制剂的发现和优化。
- 作者列表："Li G","Meanwell NA","Krystal MR","Langley DR","Naidu BN","Sivaprakasam P","Lewis H","Kish K","Khan JA","Ng A","Trainor GL","Cianci C","Dicker IB","Walker MA","Lin Z","Protack T","Discotto L","Jenkins S","Gerritz SW","Pendri A
:The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.
: HIV-1 感染的标准治疗，高效抗逆转录病毒疗法 (HAART)，结合至少两个类别的两种或两种以上药物。即使 HAART 取得成功，也需要具有新机制的新药来对抗病毒耐药性、提高依从性和减轻毒性。HIV-1 整合酶的活性部位抑制剂被临床验证用于治疗 HIV-1 感染。在这里，我们描述了 HIV-1 整合酶的变构抑制剂，它与 LEDGF/p75 相互作用位点结合，破坏了 HIV-1 成熟所需的整合酶多聚体的结构。以吡唑并嘧啶为基础的抑制剂系列，采用结构导向化合物设计优化的 2 位载体。这导致了吡唑并嘧啶 3 的发现, 在 2 和 7 位进行了优化，以提供 26 和 29 种有效的 HIV-1 整合酶变构抑制剂，在细胞培养中表现出低纳摩尔抗病毒效力，并鼓励 PK 特性。
METHODS:BACKGROUND:Ultrasound has been demonstrated to accurately diagnose rectal deep endometriosis (DE) and pouch of Douglas (POD) obliteration. The role of ultrasound in the assessment of patients who have undergone surgery for rectal DE and POD obliteration has not been evaluated. AIM:To describe the transvaginal ultrasound (TVS) findings of patients who have undergone rectal surgery for DE. MATERIALS AND METHODS:An observational cross-sectional study at a tertiary care centre in Sydney, Australia between January and April 2017. Patients previously treated for rectal DE (low anterior resection vs rectal shaving/disc excision) were recruited and asked to complete a questionnaire on their current symptoms. On TVS, POD state and rectal DE were assessed. Correlating recurrence of POD obliteration and/or rectal DE to surgery type and symptoms was done. RESULTS:Fifty-six patients were contacted; 22/56 (39.3%) attended for the study visit. Average interval of surgery to study visit was 52.8 ± 24.6 months. Surgery type breakdown was as follows: low anterior resection (56%) and rectal shaving/disc excision (44%). The prevalence of POD obliteration was 16/22 (72.7%) intraoperatively and 8/22 (36.4%) at study visit, as per the sliding sign. Nine patients (39.1%) had evidence on TVS of recurrent rectal DE. Recurrence of POD obliteration and rectal DE was not associated with surgery type or symptomatology. CONCLUSION:Despite surgery for rectal DE, many patients have a negative sliding sign on TVS, representing POD obliteration, and rectal DE. Our numbers are too small to correlate with the surgery type or their current symptoms.
METHODS::Minimally invasive surgery for complex endometriosis requires preoperative planning that intimately connects the gynecologic surgeon to the radiologist. Understanding the surgeon's perspective to endometriosis treatment facilitates a productive relationship that ultimately benefits the patient. We examine minimally invasive surgery for endometriosis and the key radiologic information which enable the surgeon to successfully negotiate patient counseling, preoperative planning, and an interdisciplinary approach to surgery.
METHODS:STUDY OBJECTIVE:Prior research collectively shows that endometriosis is inversely related to women's adiposity. The aim of this study was to assess whether this inverse relationship holds true by disease severity and typology. DESIGN:Cross sectional study among women with no prior diagnosis of endometriosis. SETTING:Fourteen clinical centers in Salt Lake City, Utah and San Francisco, California. PATIENTS:Four hundred and ninety five women, ages 18-44 years, were enrolled in the operative cohort of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study. INTERVENTIONS:Gynecologic laparoscopy/laparotomy, regardless of clinical indication. MEASUREMENTS AND MAIN RESULTS:Participants underwent anthropometric assessments, body composition, and body fat distribution ratios before surgery. Surgeons completed a standardized operative report immediately after surgery to capture revised ASRM staging (I to IV) and typology of disease (superficial [SE], ovarian endometrioma [OE], and deep infiltrating endometriosis [DIE]). Linear mixed models, taking into account within-clinical-center correlation were used to generate least square means (95% confidence intervals) to assess differences in adiposity measures by endometriosis stage (no endometriosis, I-IV) and typology (no endometriosis, SE, DIE, OE, OE + DIE) adjusting for age, race/ethnicity, and parity. While the majority of confidence intervals were wide and overlapping, three general impressions emerged: 1) women with versus without incident endometriosis had the lowest anthropometric/body composition indicators; 2) women with stage I or IV had lower indicators compared to women with stage II or III; and 3) women with OE and/or DIE tended to have the lowest indicators, while women with SE had the highest indicators. CONCLUSION:Our research highlights that the relationship between women's adiposity and endometriosis severity and typology may be more complicated than prior research indicates.