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Due to emergence of drug resistance and drug tolerability, there is urgent need for discovery of new chemical entity for the treatment of HIV infection. As a part of in-house small molecule drug discovery program for HIV infection, sodium-2-(tert-butoxy)- 2-(5-(2-(2-chloro-6-methylbenzyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)- 4-(4,4-dimethylpiperidin-1-yl)- 2,6-dimethylpyridin-3-yl) acetate (SCMTDDA) was prepared as an intermediate for the synthesis of an API, designed as a HIV-1 integrase inhibitor. Initially, the final compound was isolated as a mixture of rotamers. In the current study, we have developed a simple and efficient achiral, reversed phase (RP) HPLC method to separate the interconvertible rotamers of SCMTDDA. The effect of several parameters, including stationary phase, buffer, modifiers and column temperature, were optimized for the chromatographic separation and it was observed that best separation was achieved on a SunFire C18 column using TFA/acetonitrile (ACN) - methanol (MeOH) (1:1 v/v) as the mobile phase at 10

The progressive nature of type 2 diabetes mellitus (T2DM) renders the shifting of patients from oral drugs to insulin therapy an inevitability in most patients especially in those with long duration of diabetes. At the turn of the last millennium, neutral protamine Hagedorn (NPH) insulin was still the only long-acting insulin available for people with diabetes. The advent of the first truly long-acting basal insulin, i.e. insulin glargine 100 U/mL (Gla-100) brought to the table a remarkably long duration of action and a very minimal risk of hypoglycemia by due to less pronounced peaks in their action profile. Further, in trying to achieve fasting normoglycemia, Gla-100 has demonstrated remarkably more holistic glucose-lowering efficacy in several pivotal trials compared to other insulin formulations, such as premixed insulin and coformulations-apart from NPH insulin. This article delineates clinical data on the effectiveness of Gla-100 vs. other insulin formulations in the context of T2DM.

Background Improving the health of women before pregnancy and throughout a woman’s lifespan could mitigate disparities and improve the health and wellbeing of women, infants and children. The preconception period is important for reducing health risks associated with poor maternal, perinatal and neonatal outcomes, and eliminating racial and ethnic disparities in maternal and child health. Low cost health information technology interventions provided in community-based settings have the potential to reach and reduce disparities in health outcomes for socially disadvantaged, underserved and health disparity populations. These interventions are particularly important for Black and African American women who have a disproportionate burden of pregnancy-related complications and infant mortality rates compared to any other racial and ethnic group in the U.S. Methods This is a hybrid type II implementation-effectiveness cohort study aimed at evaluating appropriateness, acceptability and feasibility implementation outcomes, while also systematically examining the clinical effectiveness of a preconception care (PCC) intervention, the Gabby System, for Black and African American women receiving health services in community-based sites. The intervention will be implemented in six Community Health Centers and six Healthy Start programs across the U.S. Each study site will recruit and enroll 25–50 young Black and African American women who will participate in the intervention for a 6-month period. Appropriateness, acceptability and feasibility of implementing the PCC intervention will be assessed using: 1) Qualitative data derived from individual interviews with Gabby System end-users (clients and patients) and site staff; and, 2) Quantitative data from staff surveys, Gabby System usage and uptake. Aggregate health risk and utilization measures collected directly from the Gabby server will be used to examine the effectiveness of the Gabby System on self-reported behavior change. Discussion This study will examine implementation outcomes and clinical effectiveness of an evidence-based PCC intervention for Black and African American women receiving services in Healthy Start programs and Community Health Centers. Contextual factors that influence uptake and appropriate implementation strategies will be identified to inform future scalability of the intervention. Trial registration ClinicalTrials.gov NCT04514224. Date of registration: August 14, 2020. Retrospectively Registered.

Summary Background Preconception care focuses on improving women's health before pregnancy as a means to improve their health and future pregnancy outcomes. How to effectively deliver such care is unknown. The aim of this research was to assess the impact of an embodied conversational agent system on preconception risks among African American and Black women. Methods We did an open-label, randomised controlled trial of women aged 18–34 years, self-identified as African American or Black, or both, and not pregnant, recruited from 35 states in the USA. Sealed allocation envelopes (in permuted blocks of six and eight, prepared using a random number generator) were opened after enrolment. Intervention participants received an online conversational agent called Gabby that assessed 102 preconception risks and delivered 12 months of tailored dialogue using synthesised speech, non-verbal behaviour, visual aids, and health behaviour change techniques such as motivational interviewing. The control group received a letter listing their preconception risks and encouraging them to talk with a clinician. The primary outcome was the proportion of identified risks at the action or maintenance stage of change at months 6 and 12. The study is registered with ClinicalTrials.gov, NCT01827215. Findings From March 11, 2014, through July 8, 2018, 528 women recruited from 35 states and 242 cities across the USA received the Gabby intervention (n=262) or were assigned to the control group (n=266). Participants identified a mean of 21 preconception risks per woman (SD 9·9). In the intention-to-treat analysis, at 6 months, intervention women reported reaching the action or maintenance stage of change for 50·0% (SD 28·9) of those preconception risks identified compared with 42·7% (28·3) in the control group (incidence rate ratio 1·16, 95% CI 1·07–1·26; p=0·0004). This result persisted at 12 months. Interpretation The Gabby system has the potential to improve women's preconception health. Further research is needed to determine if improving preconception risks impacts outcomes such as preterm delivery. Funding National Institute for Minority Health and Health Disparities.

A preconception Virtual Patient Advocate (VPA) called “Gabby” supported African-American women to decrease their preconception health risks and may be a scalable resource to increase women’s access to preconception care. Aims were to assess the acceptability of a preconception VPA in women living in Australia and document the changes required to adapt Gabby to suit an Australian context. Taking a descriptive qualitative approach, nonpregnant female participants (n = 31), aged 18–45 years, living in metropolitan and regional Victoria, Australia interacted with Gabby. Focus groups (n = 7) that gathered participants’ perspectives of their experience with Gabby ran in July–August 2019 before being transcribed verbatim and thematically analyzed. Six interrelated themes and 12 subthemes were identified. Participants found VPAs to be an acceptable provider of health information with potential to increase women’s access preconception health advice. Gabby was considered to be trustworthy and was able to develop rapport with participants in a relatively short time. Context-specific, relevant, tailored and trustworthy information and advice were considered more important that Gabby’s physical appearance. Participants had strong opinions about potential technological advancements (e.g., reminders and rewards) and addressing navigation issues to increase Gabby’s acceptability. Participants envisaged that they would use Gabby for readily available and evidence-based information before seeking advice from a health professional if required. Overall, the concept VPAs to provide preconception advice and Gabby were acceptable to participants. Future development of VPAs, Gabby, and other online technology-based resources should consider women’s high expectations of the online health information they choose to interact with.

Additional file 3. Quantitative readiness assessment survey. This readiness assessment is used to concurrently assess organizational readiness and identify barriers and facilitators to implementation. Survey administered using Qualtrics XM®.

Additional file 6. Organizational stakeholder post implementation interview guide. This guide is used to assess leadership, clinical, and administrative staffs’ perceptions of Gabby and the process of implementing the Gabby System as well as recommendations for scalability.

Additional file 4. Technical assistance semi-structured interview guide. This tool is used to facilitate phone calls with site champions and staff engaged in implementation efforts to capture progress of recruitment and implementation efforts.

Additional file 2. Organizational readiness assessment interview guide. Grounded in the CFIR this tool is used to assess organizational readiness and identify barriers and facilitators to implementation.

Additional file 7. End-user post implementation interview guide. This guide is used to examine end-users’ experiences using Gabby, and better understand the context in which implementation occurred from the end-user perspective.

Additional file 5. Monthly implementation log. This tool is used to assess engagement and enrollment of end-users from the perspective of staff and to capture technical issues that end-users and staff encounter during implementation.

Additional file 1. Organizational parameter survey. Survey used to collect in-depth information about the organization’s characteristics. Survey administered using Qualtrics XM®.

A significant number of secondary hypertension could be due to endocrine etiology. The pheochromocytoma/paraganglioma (PGL) syndrome is one among them. We herein report a case of PGL in a young woman, who presented to us with hypertension and its reversal after surgical treatment. In this review, we also discussed in detail about this rare entity.

Discovery, optimization, and early development of drug candidates are very challenging and require a versatile synthetic chemistry toolbox. Organozinc chemistry is a powerful methodology for carbon–carbon bond formation which tolerates several functional groups that are critical for maintaining good physicochemical properties of drug molecules. Here we demonstrate that organozinc chemistry offers facile solutions to otherwise challenging medicinal chemistry problems commonly encountered during lead optimization. In this review, we summarize several examples in which utilization of organozinc-mediated couplings enabled us to rapidly explore a medicinal chemistry hypothesis using readily available intermediates. This chemistry allowed us to make rapid decisions with limited chemistry resources. 1 Introduction 2.1 Alpha4 Integrin Antagonists 2.2 CRTH2 Antagonists 2.3 Glucokinase (GK) Activators 2.4 Leukotriene B4 (LTB4) Receptor Antagonists 2.5 Janus Activated Kinase 3 (JAK3) Inhibitors 2.6 Synthesis of Novel Scaffolds 3 Conclusions 4 Experimental Methods

From a series of N-acyl 4-(3-pyridonyl)phenylalanine derivatives of 4, the trifluoromethyl derivative 28 was identified as a potent, dual acting alpha4 integrin antagonist with activity in primate models of allergic asthma. Investigation of a series of prodrug esters led to the discovery of the morpholinopropyl derivative 48 that demonstrated good intestinal fluid stability, solubility and permeability. Compound 48 gave high blood levels of 28 when dosed orally in cynomolgus monkeys. Surprisingly, hydrolysis of 48 was rapid in liver microsomes from the pharmacological species, mouse, rat and monkey, but slow in dog and human; in vivo studies also indicated there was prolonged exposure to unchanged prodrug in dogs.

N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4β1 and α4β7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.

Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF.

The synthesis of various aryl methyl sulfides has been achieved by treatment of nitroarenes with a combination of (methylthio)trimethylsilane and cesium carbonate in dimethylsulfoxide. This reaction gives access to aryl methyl sulfide derivatives in high yields.

The phenylacetamide 1 represents the archtypical glucokinase activator (GKA) in which only the R -isomer is active. In order to probe whether the chiral center could be replaced, we prepared a series of olefins 2 and show in the present work that these compounds represent a new class of GKAs. Surprisingly, the SAR of the new series paralleled that of the saturated derivatives with the exception that there was greater tolerance for larger alkyl and cycloalkyl groups at R 2 region in comparison to the phenylacetamides. In normal Wistar rats, the 2,3-disubstituted acrylamide analog 10 was well absorbed and demonstrated robust glucose lowering effects.

The inhibition of LTB(4) binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B(4) (LTB(4)) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB(4) binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB(4) and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.

A novel series of quinolinyl-methylene-thiazolinones has been identified as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Their synthesis and structure activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK1 activity in vitro, and block cell cycle progression in human tumor cell lines, suggesting a potential use as antitumor agents.

Starting with a cyclic peptide of moderate potency as a VLA-4 antagonist, highly potent and conformationally defined cyclic peptides were developed incorporating a constrained tyrosine and an achiral Asp-Pro spacer. N-Acyl phenylalanine derivatives were also discovered to have VLA-4 antagonist activity. During the course of development of this series, we found that the active acylphenylalanines mimic the pharmacophores present in the cyclic peptides and hypothesized that they bind to the same site on VLA-4. This insight guided our optimization strategy. Based on the emerging SAR, as well as insights from the recent X-ray crystal structure of the integrin alphavbeta3 bound to a RGD containing cyclic peptide, we propose a binding model for these compounds.

A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-L-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (-) bioactive conformation.

A series of N-benzoyl-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine derivatives was prepared in order to optimize the substitution on the N-benzoyl moiety for VCAM/VLA-4 antagonist activity. Disubstitution in the 2- and 6-positions is favored and a range of small alkyl and halogen are tolerated. A model of the bioactive conformation of these compounds is proposed.

Discovery, optimization, and early development of drug candidates are very challenging and require a versatile synthetic chemistry toolbox. Organozinc chemistry is a powerful methodology for carbon–carbon bond formation which tolerates several functional groups that are critical for maintaining good physicochemical properties of drug molecules. Here we demonstrate that organozinc chemistry offers facile solutions to otherwise challenging medicinal chemistry problems commonly encountered during lead optimization. In this review, we summarize several examples in which utilization of organozinc-mediated couplings enabled us to rapidly explore a medicinal chemistry hypothesis using readily available intermediates. This chemistry allowed us to make rapid decisions with limited chemistry resources. 1 Introduction 2.1 Alpha4 Integrin Antagonists 2.2 CRTH2 Antagonists 2.3 Glucokinase (GK) Activators 2.4 Leukotriene B4 (LTB4) Receptor Antagonists 2.5 Janus Activated Kinase 3 (JAK3) Inhibitors 2.6 Synthesis of Novel Scaffolds 3 Conclusions 4 Experimental Methods

High throughput screening (HTS) of our chemical library identified 3-alkylamino-2-aryl-5H-imidazo[1,2,b]pyrazol-7-carbonitrile 1 as a potent antagonist of the LPA1 receptor (LPA1R). Further evaluation of this class of compounds indicated that LPA1R antagonist activity originated from the degradation of the parent molecule in DMSO during the assay conditions. Here, we describe the isolation and characterization of the degradation products and their LPA1R antagonist activity. We further profiled these novel non-carboxylic acid LPA1R antagonists and demonstrated their inhibition of LPA-induced proliferation and contraction of normal human lung fibroblasts (NHLF).

An unexpectedly low N-9/N-7 regioselectivity was obtained when Robins' reagent (2-N-acetyl-6-O-diphenylcarbamoylguanine) was coupled with a d -glucosamine derivative under trimethylsilyl trifluoromethanesulfonate activation. An unprecedented solvent effect (toluene versus dichloroethane) on the N-9/N-7 ratio was also observed in the same study. The use of 2-N-acetyl-6-O-benzylguanine to successfully overcome the above regioselectivity problem is described.