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Applying Screening Techniques to Two Orphan Gpcrs
Universidade de Lisboa Faculdade de Farmácia Deorphanization of receptors: Applying screening techniques to two orphan GPCRs Ana Catarina Rufas da Silva Santos Mestrado Integrado em Ciências Farmacêuticas 2019 Universidade de Lisboa Faculdade de Farmácia Deorphanization of receptors: Applying screening techniques to two orphan GPCRs Ana Catarina Rufas da Silva Santos Monografia de Mestrado Integrado em Ciências Farmacêuticas apresentada à Universidade de Lisboa através da Faculdade de Farmácia Orientadora: Ghazl Al Hamwi, PhD Student Co-Orientadora: Professora Doutora Elsa Maria Ribeiro dos Santos Anes, Professora Associada com Agregação em Microbiologia 2019 Abstract G-Protein Coupled Receptors represent one of the largest families of cellular receptors discovered and one of the main sources of attractive drug targets. In contrast, it also has a large number of understudied or orphan receptors. Pharmacological assays such as β-Arrestin recruitment assays, are one of the possible approaches for deorphanization of receptors. In this work, I applied the assay system previously mentioned to screen compounds in two orphan receptors, GRP37 and MRGPRX3. GPR37 has been primarily associated with a form of early onset Parkinsonism due to its’ expression patterns, and physiological role as substrate to ubiquitin E3, parkin. Although extensive literature regarding this receptor is available, the identification of a universally recognized ligand has not yet been possible. Two compounds were proposed as ligands, but both were met with controversy. These receptor association with Autosomal Recessive Juvenile Parkinson positions it as a very attractive drug target, and as such its’ deorphanization is a prime objective for investigators in this area. Regarding MRGPRX3 information is much scarcer. -
Fig. L COMPOSITIONS and METHODS to INHIBIT STEM CELL and PROGENITOR CELL BINDING to LYMPHOID TISSUE and for REGENERATING GERMINAL CENTERS in LYMPHATIC TISSUES
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date Χ 23 February 2012 (23.02.2012) WO 2U12/U24519ft ft A2 (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/00 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US201 1/048297 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 18 August 201 1 (18.08.201 1) NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/374,943 18 August 2010 (18.08.2010) US kind of regional protection available): ARIPO (BW, GH, 61/441,485 10 February 201 1 (10.02.201 1) US GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 61/449,372 4 March 201 1 (04.03.201 1) US ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventor; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, (71) Applicant : DEISHER, Theresa [US/US]; 1420 Fifth LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Avenue, Seattle, WA 98101 (US). -
Preladenant | Medchemexpress
Inhibitors Product Data Sheet Preladenant • Agonists Cat. No.: HY-10889 CAS No.: 377727-87-2 Molecular Formula: C₂₅H₂₉N₉O₃ • Molecular Weight: 503.56 Screening Libraries Target: Adenosine Receptor Pathway: GPCR/G Protein Storage: Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month SOLVENT & SOLUBILITY In Vitro DMSO : 5 mg/mL (9.93 mM; Need ultrasonic) Mass Solvent 1 mg 5 mg 10 mg Concentration Preparing 1 mM 1.9859 mL 9.9293 mL 19.8586 mL Stock Solutions 5 mM 0.3972 mL 1.9859 mL 3.9717 mL 10 mM --- --- --- Please refer to the solubility information to select the appropriate solvent. In Vivo 1. Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline Solubility: 0.5 mg/mL (0.99 mM); Suspended solution; Need ultrasonic 2. Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline) Solubility: 0.5 mg/mL (0.99 mM); Suspended solution; Need ultrasonic 3. Add each solvent one by one: 10% DMSO >> 90% corn oil Solubility: ≥ 0.5 mg/mL (0.99 mM); Clear solution BIOLOGICAL ACTIVITY Description Preladenant is a potent and competitive antagonist of the human adenosine A2A receptor with a Ki of 1.1 nM and has over 1000-fold selectivity over other adenosine receptors. [1] IC₅₀ & Target Ki: 1.1 nM (Adenosine A2A receptor) In Vitro Preladenant also completely antagonizes cAMP in cells expressing the recombinant human A2A receptor. Preladenant is determined to has KB values of 1.3 nM at the A2A receptor; the value is in good agreement with the Ki value determined in Page 1 of 3 www.MedChemExpress.com the radioligand binding assay. -
Targeted Review List Kaiser HMO, Multi-Choice, PPO, Senior Advantage Effective 1/01/2020
Kaiser Permanente Georgia Region Provider Targeted Review List Kaiser HMO, Multi-Choice, PPO, Senior Advantage Effective 1/01/2020 The Affiliated Community Physician is responsible for verification of member eligibility and benefit coverage by logging on to KP Online-Affiliate or calling Member Services at 404-261- 2590. Failure to obtain authorization prior to providing the services listed below will result in a denial of payment. A medical necessity review decision will be issued to your office and to the member upon completion of the review process. Receipt of complete clinical information with the initial request will expedite the process. Authorization for approval of services based on medical necessity is never a guarantee of payment which must also meet the criteria of member eligibility and benefit availability. The Kaiser Permanente Quality Resource Management Department requires authorization of all post stabilization care including observation and inpatient admissions. Please call our Emergency Care Management hub at 404-365-4254 for authorization. For emergency authorization of home health or durable medical services after regular business hours, contact 404-365-0966 or 800-611-1811 to speak with the QRM case manager on call. Hours of Operation: Quality Resource Management Department Monday through Friday 8:00 am – 5:00 pm 404-364-7320/800-221-2412 Member Services Department Monday through Friday 7:00 am – 7:00 pm 404-261-2590 Emergency Care Management Hub Available 24/7 404-365-4254 Medical necessity review is required for the following services/conditions: HMO members require QRM review and approval for reimbursement of any non- contracted, out of network (office based, outpatient, inpatient) services. -
Challenges and Approaches for the Development of Safer Immunomodulatory Biologics
REVIEWS Challenges and approaches for the development of safer immunomodulatory biologics Jean G. Sathish1*, Swaminathan Sethu1*, Marie-Christine Bielsky2, Lolke de Haan3, Neil S. French1, Karthik Govindappa1, James Green4, Christopher E. M. Griffiths5, Stephen Holgate6, David Jones2, Ian Kimber7, Jonathan Moggs8, Dean J. Naisbitt1, Munir Pirmohamed1, Gabriele Reichmann9, Jennifer Sims10, Meena Subramanyam11, Marque D. Todd12, Jan Willem Van Der Laan13, Richard J. Weaver14 and B. Kevin Park1 Abstract | Immunomodulatory biologics, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions — including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity — pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics. Immunomodulatory Biologics currently represent more than 30% of licensed The high specificity of the interactions of immu- biologics pharmaceutical products and have expanded the thera- nomodulatory biologics with their relevant immune Biotechnology-derived peutic options available -
1.Intro Corregida
Heterómeros de receptores de dopamina como dianas terapéuticas en la enfermedad de Parkinson y en discinesias inducidas por el tratamiento con L-DOPA Daniel Farré Pérez ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB. -
WHO EML Application Tocilizumab
WHO EML Application Tocilizumab Condition Juvenile Idiopathic Arthritis 1 Summary statement of the proposal for inclusion. The application proposes the inclusion of Tocilizumab on the complementary list of the EML/EMLc/both for the treatment of Systemic Onset Juvenile Idiopathic Arthritis (SOJIA). The rationale for the complementary list is that the use of this drug requires specialised care. The proposed listing on both the EML and EMLc reflects the fact that JIA affects children through adolescence and into adulthood. This rationale is consistent with the listing for the anti-TNF biologics currently listed for JIA. Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatic disease of childhood, affecting approximately one per 1000 children (1, 2). JIA is characterised by joint inflammation of more than 6 weeks’ duration, with onset before age sixteen years and where no other cause is found (2). JIA is an autoimmune, non-infective, inflammatory joint disease, the cause of which remains poorly understood with both genetic and environmental contributions (3). It is a distinct entity from rheumatoid arthritis, differing in clinical presentations, prognosis, disease outcomes and treatment approaches. The age of onset in JIA is typically young, with a peak incidence between 1-3 years of age, although the disease persists into adulthood in approximately 50% of cases (4). Even in patients in whom the inflammatory disease resolves, joint or extra-articular damage – with associated disability – are common and if not treated then can result in irreversible sequelae and impact on quality of life (5). Current treatment approaches for children with JIA aim for normal physical and psychosocial functioning, and with access to modern treatments, good outcomes are a realistic and achievable goal for many children with this condition (6) . -
Specialty Guideline Management
Reference number 1800-A SPECIALTY GUIDELINE MANAGEMENT ARCALYST (rilonacept) POLICY I. INDICATIONS The indications below including FDA-approved indications and compendial uses are considered a covered benefit provided that all the approval criteria are met and the member has no exclusions to the prescribed therapy. FDA-Approved Indications Treatment of Cryopyrin Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 12 years of age and older. All other indications are considered experimental/investigational and not medically necessary. II. CRITERIA FOR INITIAL APPROVAL Cryopyrin-associated periodic syndrome (CAPS) Authorization of 12 months may be granted for treatment of CAPS when all of the following criteria are met: A. Member has a diagnosis of familial cold auto-inflammatory syndrome (FCAS) with classic signs and symptoms (i.e., recurrent, intermittent fever and rash that were often exacerbated by exposure to generalized cool ambient temperature) or Muckle-Wells syndrome (MWS) with classic signs and symptoms (i.e., chronic fever and rash of waxing and waning intensity, sometimes exacerbated by exposure to generalized cool ambient temperature). B. Member has functional impairment limiting the activities of daily living. III. CONTINUATION OF THERAPY Authorization of 12 months may be granted for all members (including new members) who are using the requested medication for an indication outlined in Section II and who achieve or maintain positive -
The Two Tondition to Martin
THETWO TONDITIONUS 20170306038A1 TO MARTIN ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2017/ 0306038 A1 BROGDON et al. (43 ) Pub . Date : Oct. 26 , 2017 ( 54 ) COMPOSITIONS AND METHODS OF USE Publication Classification FOR AUGMENTED IMMUNE RESPONSE (51 ) Int. Cl. AND CANCER THERAPY CO7K 16 / 28 ( 2006 .01 ) (71 ) Applicants : Jennifer BROGDON , Sudbury , MA CO7K 16 / 28 ( 2006 . 01) (US ) ; Daniela CIPOLLETTA , A61K 45 / 06 (2006 . 01 ) Arlington , MA (US ) ; Glenn A61K 39 /00 ( 2006 .01 ) DRANOFF , Lexington , MA ( US ) ; A61K 39 /00 (2006 .01 ) Deborah A . KNEE . Del Mar. CA (US ): (52 ) U . S . Cl. CPC . .. .. CO7K 16 / 2878 ( 2013. 01 ) ; C07K 16 /2818 Fei WANG , San Diego , CA (US ) ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; CO7K ( 72 ) Inventors : Jennifer BROGDON , Sudbury , MA 2317 / 74 ( 2013 . 01 ) ; C07K 2317 / 732 ( 2013 .01 ) ; (US ) ; Daniela CIPOLLETTA , CO7K 2317 / 567 ( 2013 . 01 ) ; COZK 2317 / 56 Arlington , MA (US ) ; Glenn ( 2013 .01 ) ; CO7K 2317 /51 ( 2013 .01 ) ; CO7K DRANOFF , Lexington , MA (US ) ; 2317 / 24 (2013 .01 ) ; A61K 2039 /507 (2013 . 01 ) ; Deborah A . KNEE , Del Mar, CA (US ) ; A61K 2039 /505 ( 2013 . 01 ) ; COZK 2317 / 75 ( 2013 . 01 ) ; CO7K 2317/ 92 ( 2013 .01 ) ; CO7K Fei WANG , San Diego , CA (US ) 2317/ 515 (2013 . 01) ( 21 ) Appl. No. : 15 /517 ,872 (57 ) ABSTRACT (22 ) PCT Filed : Oct . 8 , 2015 The present invention provides antibody compositions , (86 ) PCT No. : PCT/ US2015 / 054770 including , e . g ., antibodies, engineered antibodies and anti body fragments that bind to a tumor necrosis factor receptor $ 371 ( c ) ( 1 ), superfamily member ( i. e . , 18 ) , and compositions comprising ( 2 ) Date : Apr. -
(12) United States Patent (10) Patent No.: US 9.402,830 B2 Cialella Et Al
USOO940283OB2 (12) United States Patent (10) Patent No.: US 9.402,830 B2 Cialella et al. (45) Date of Patent: * Aug. 2, 2016 (54) METHODS OF TREATING DYSKINESIA AND FOREIGN PATENT DOCUMENTS RELATED DSORDERS WO 93.18767 A1 9, 1993 (71) Applicant: Melior Discovery, Inc., Exton, PA (US) OTHER PUBLICATIONS (72) Inventors: John Ciallella, Exton, PA (US); John Afanasev et al., Effects of amphetamine and Sydnocarbon dopamine Gruner, Exton, PA (US); Andrew G. release and free radical generation in rat striatum, Pharmacol Reaume, Exton, PA (US); Michael S. Biochem Behav, 2001, 69(3-4):653-8. Saporito, Exton, PA (US) Anderzhanova et al., Effect of d-amphetamine and Sydnocarb on the extracellular level of dopamine, 3,4-dihydroxyphenylacetic acid, and (73) Assignee: Melior Discovery, Inc., Exton, PA (US) hydroxyl radicals generation in rat striatum, Ann NY AcadSci, 2000, 914:137-45. Anderzhanova et al., Effects of Sydnocarb and D-amphetamine on the (*) Notice: Subject to any disclaimer, the term of this extracellular levels of amino acids in the rat caudate-putamen, Eur J patent is extended or adjusted under 35 Pharmacol, 2001, 428(1):87-95. U.S.C. 154(b) by 0 days. Bashkatova et al., Neuroshemical changes and neurotoxic effects of This patent is Subject to a terminal dis an acute treatment with Sydnocarb, a novel psychostimulant: com claimer. parison with D-amphetamine, Ann NY AcadSci, 2002,965: 180-192. Cody, Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results, J Occup Environ Med, (21) Appl. No.: 14/702,242 2002, 44(5):435-50. -
Prior Authorization Policy
PRIOR AUTHORIZATION POLICY POLICY: Inflammatory Conditions – Arcalyst® (rilonacept for subcutaneous injection Regeneron Pharmaceuticals) DATE REVIEWED: 11/06/2019; selected revision 04/01/2020 OVERVIEW Arcalyst is an interleukin-1 (IL-1) blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children aged 12 years and older.1 Arcalyst, also known is a recombinant dimeric fusion protein that blocks IL-1β signaling and to a lesser extent also binds IL-1α and IL-1 receptor antagonist (IL-1ra). In adults ≥ 18 years of age, Arcalyst is initiated with a loading dose of 320 mg delivered as two subcutaneous (SC) injections of 160 mg on the same day at two separate sites. Dosing is continued with 160 mg once weekly as a single injection. In adolescents aged 12 to 17 years, therapy is initiated with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two SC injections with a maximum single-injection volume of 2 mL. If the initial dose is two injections, then patients should be given Arcalyst on the same day at two separate sites. In adolescents, dosing is continued with 2.2 mg/kg, up to a maximum of 160 mg, once weekly as a single injection. Disease Overview CAPS is a rare inherited inflammatory disease associated with overproduction of IL-1. CAPS encompasses three rare genetic syndromes. FCAS, MWS, and neonatal onset multisystem inflammatory disorder (NOMID) or chronic infantile neurological cutaneous and articular syndrome (CINCA) are thought to be one condition along a spectrum of disease severity.2-3 FCAS is the mildest phenotype and NOMID is the most severe. -
Chemical Properties Biological Description
Data Sheet (Cat.No.T4290) Preladenant Chemical Properties CAS No.: 377727-87-2 Formula: C25H29N9O3 Molecular Weight: 503.57 Appearance: N/A Storage: 0-4℃ for short term (days to weeks), or -20℃ for long term (months). Biological Description Description Preladenant is an orally bioavailable antagonist of the adenosine A2A receptor (Ki: 1.1 nM) and has >1000-fold selectivity over all other adenosine receptors. Targets(IC50) A2A: None In vitro In cells expressing the recombinant human A2A receptor, Preladenant completely antagonizes cAMP. The KB values of Preladenant is 1.3 nM at the A2A receptor. A similar functional assay with A2B receptor-expressing cells is used to demonstrate selectivity over A2B receptors. In this assay, the KB value for Preladenant is 1.2 μM and this selectivity for the A2A receptor is 923-fold over the A2B receptor. In vivo Preladenant (1 mg/kg) inhibits L-Dopa-induced behavioral sensitization. In the mouse tail suspension test and the mouse and rat forced swim test, Preladenant exhibits antidepressant-like profiles. Preladenant dose- dependently reduces the parkinsonian scores at doses of 1 mg/kg (min score: 9.0) and 3 mg/kg (min score: 6.5). A subthreshold dose of Preladenant reduces minimum and mean parkinsonian scores in animals treated with 3 mg kg of L-Dopa to 5.25 and 6.88 respectively. A Wilcoxin test is used to compare individual treatments against the vehicle. Preladenant (3 mg/kg), L-Dopa (3, 6, and 12 mg/kg), and the combination of Preladenant and L- Dopa (1 or 3 mg/kg+3 mg/kg) are all significantly improved on the minimum parkinsonian score.