Baran Group Meeting Lisa M. Barton G Protein-Coupled Receptor Drugs 5/4/19 Introduction GPCR Classes • G Protein-Coupled Receptors (GPCRs) are very important for human biology A-F System: Based on amino - Largest family of membrane-bound receptors acid sequences and functional - Over 350 non-olfactory GPCRs in humans, ~1/3 similarities, covers GPCRs in of which have been drugged invertebrates and vertebrates - Expressed on all cells in the body - Regulate numerous diverse physiological Class A or Rhodopsin processes including intercellular Class B or Secretin communication and signal transmission Class C or Glutamate - Over 30% of approved drugs target GPCRs Class D or Fungal Mating - Between 2011-2015 represented ~27% of the Pheromone (not in vertebrates) global market share of therapeutic drugs and Class E or cAMP receptors generated ~$890 billion (not in vertebrates) Class F or Frizzled/smoothened receptors GRAFS System: Based on phylogenetic tree, covers only human GPCRs G or Glutamate R or Rhodopsin A or Adhesion F or Frizzled/Taste2 S or Secretin From Trends in Pharm. Sci. 2012, 33, 17 Mol. Pharma. 2003, 63, 1256 Definitions • Agonist - mimic function of natural ligands by binding to receptor and causing the normal response • Partial Agonist - any agonist that produce the maximum response capable in a system even at saturating From Nat. Rev. Drug Discov. 2017, 16, 829 concentrations • Most GPCR-targeting drugs were not initially devoped to target a specific protein but • Antagonist - bind to receptor and prevent normal response rather by functional activity by inhibiting natural ligand from binding; keeps response of • Increase in GPCR crystal structures (>40), advances in receptor at basal levels. Could be either competitive biophysical techniques, and computational methods has (reversible) or non-competitive (irreversible). led to increases in structure-based drug discovery • Inverse Agonist - different than simple antagonist as will • 1967, 1970 1971, 1988, 1994, 2000, 2004 and 2012 switch a receptor into an "off" state; this cause a response Novel Prizes were awarded for GPCR related research that lowers response bellow basal levels • Allosteric Inhibitor - acts by binding to a site that is Group Meeting Includes topographically disctint from, but conformationally linked to, • Introduction to GPCRs, their structure, and the active site basic functions • Potency - the dose range over which a response is • Adrenergic and Anglotensin Receptors produced; from a dose-reponse cure the potency is the dose • Histamine Receptors of the drug that produces 50% of the maximum response • Dopamine and 5-HT (Serotonin) Receptors (ED50) • Muscarinic Receptors Group Meeting Doesn't Include • Efficacy - the size/strength of a response produced by an • Adenosine Receptors • An exhaustive discussion of any of these agonist in a particular tissue • Opioid Receptors topics • Chemokine Receptors • Many of the lesser-targeted GPCRs With GPCR Drugs it is not always clear exactly what kind of interaction they have with a • Gonadotropin-releasing Hormone Receptors • Orphan GPCRs particular receptor and there are many cases where a drug has been re-catagorized as a better • List of Validated GPCR Drug Targets • In depth biology on individual GPCRs understanding of the mechanism of action is gained from biological studies Baran Group Meeting Lisa M. Barton G Protein-Coupled Receptor Drugs 5/4/19 Adrenergic Receptors (ARs) Structure of GPCRs Agonists: OH • Also classified as α-1 Adrenergic Recep All share same transmembrane domain • Epinephrine primarily released by the adrenal gland whereas HO NHR with common structure: Norepinephrin released by sympathetic nerve terminals in peripheral • 7 transmembrane domains that are nervous system and brain HO hydrophobic α-helices • Play key role in cardiac function • 3 extracellular loops • 2 classes: β-ARs (~90% total ARs in heart) and α-ARs (~10%) R = Me: Epinephrine • 3 intracellular loops (adrenaline) • Each classes can be further subdived into α1, α2, β1,β2 and β3 • N-terminus (responsible for ligand binding) • Targeting this GPCR class lead to development of Beta Blockers R = H: Norepinephrin • C-terminus • Drugs targeting these receptors also have indications in treatment O of asthma and COPD i OH GPCR Signaling Pathway OH PrHN Select Examples: O NHiPr N t O O NH Bu O Me N nPr N S N OH H O Acebutolol (Sectral®) Propranolol (Inderal®) Timolol (Betimol®) Sanofi AZ Akorn Pharma Angiotensin Receptors (ATs) • Angiotensin is a hormone made by the liver that is further converted to Angiotensin I and II by therenin-angiotensin enzymatic cascade • Angiotensin II plays an important role in cardiovascular system • 3 classes: AT1, AT2, and Mas which differ in their affinity for various angiotensin peptide fragments • Targeting this GPCR class lead to development of Angiotensin II Receptor Blockers (ARBs); unlike ACE inhibitors (which only can prevent the formation of angiotensin by the renin-angiotensin enzymatic cascade) these can block all angiotensin as they prevent their binding to receptors HN NH2 NH OH Agonists: N From Exp. Mol. Med. 2016, 48, e207 • GPCRs in constant motion HO Angiotensin II O O O N O • Agonist binding stabalizes GPCR into "On" conformation H H H HO N N • Agonists can range from ions and small molecules to peptides and large proteins depending N N N O on the type of receptor HN O NH H O H O H N • "On" conformation further stabalized by binding of G-protein (made up of α, β and γ subunits) 2 Me Me Me O • Note little is known about how GPCRs associate with specific G-proteins Select Examples: HO C Me • Once G protein encounters ligand-bound GPCR, GDP is exchanged with GTP; triggers 2 N N N NH release of Gβγ dimer. Cl N •MsOH N NH nBu • Both free Gα and Gβγ can interact with effector molecules in cells, trigger downstream signaling N N CO2H N O N nBu • Pathway stops when Gα hydrolyzes GTP to GDP and reassociates with Gβγ. N N • There are multiple pathways through which GPCRs can become desensitized, including S nBu receptor phosphorylation events, arresting-mediated internalization into endosomes, receptor OH recycling and lysosomal degradition Losartan (Cozaar®) Eprosartan Mesylate (Teveten®) Irbesartan (Avapro®) • Many GPCRs can trigger multiple different signalling pathways and specific ligands can Merck GSK Sanofi/BMS produce different relative efficacies to different pathways (sometimes even opposite, ie acting For more details on drugs that target both these receptors see Cardiovascular (CV) Drugs as both an agonist for 1 and an antagonist for another) Group Meeting (Merchant 2018) Baran Group Meeting Lisa M. Barton G Protein-Coupled Receptor Drugs 5/4/19 nd OMe Histamine Receptors 2 generation: F Astemizole Me • Histamine is naturally produced from L-histidine by histidine decarboxylase in (Hismanal®) Cl N a number of different cell types and is involved in the regulation of a number of Agonist: O H N N different body functions (ie cell proliferation, hematopoiesis, wound healing, N N sleep/wake cycle, cognition memory, etc) N NH2 N N • 4 different classes: H1-H4 HN N Azelastine Ph OH • Indications of drugs that act as histamine antagonists range from treatment Histamine (Astelin®) N of allergic conditions (H1), peptic ulcers (H2), obesity and CNS disorders (H3), R= Me: Terfenadine (Seldane®) OH Ph R and asthma and inflammation (H ) 4 For a review on Histamine Receptors see N R= CO2Et: Br. J. Pharmacol. 2006, 147, S127 Loratadine In response to external stimuli Cl Me cell release of inflammatory Me (Claritin®) mediators such as Histamine Ph Acrivastine R= CO2H R R= H: Fexofenadine Me Histamine (Benadryl Allergy Desloratadine Cytokine and chemokine production ® N Adhesion molecule production (Allegra ) Vasodilation ® (Clarinex®) Allergy and inflammation Bronchoconstriction Relief ) Vasodilation H1R Platelet aggregation N Bronchoconstriction Mucus hyper-secretion HO C O Cl Platelet aggregation HO2C N 2 N Gaq/11 racemic: chiral: Ca2+ Ca2+ Ca2+ Cetirizine (Zyrtec®) Levocetirizine (Xyzal®) H4R Gai/o Gas H2R Ca2+ OPRD 2012, 16, 1279 Gai/o Ph Ca2+ release from ER Degrannulation Gastric acid secretion OH Increase in heart rate Chemotaxis H3R Ph O CONH2 Immunomodulation and cardiac output N + Cl Sleep-wake cycle, cognition, HN (34% overall yield) Homeostatic regulation of energy levels, Cl + A Neurotransmission N Cl O + Cl O CO2Me H1 Receptors Cl A + Cl NMe • H -recptor is widely expressed (nerves, 2 N 1 H Cetirizine (10% overall yield) respiratory epithelium, endothelial cells, hepatic cells, vascular smooth muscle cells, dendritic O cells, lymphocytes) O CN O A + Cl • Involved in allergy and inflammation Ph Cl X Crystal structure of H1 receptor complexed with Ph ("good yeild") • Antihistamines all act as inverse agonists and doxepin; Nature 2011, 475, 65 + NR lock into inactive state Cl O • 1st gen histadines: sedating HN N + Cl X = ONa (56%) • 2nd gen: relatively nonsedating Cl N X X = OH (67%) • 6 Chemical Classes of Antihistamines: – Ethanolamines – Phenothiazines – Piperazines HO Cl – Ethylenediamines – Alkylamines – Piperidines Ways to make chiral (Levocetirizine): Select examples of H Antihistamines 1 O st Clemastine S 1 generation: Br N tBu 1. PhMgBr, Tol (Meclastin®) NH2 Cl -20 to 0 ºC Me Ph 65%, >99% ee Ph N N NMe2 O 2. HCl, MeOH Ph O racemic: Brompheniramine Cl 95% Cl Diphenhydramine Me Levocetirizine NMe2 (Dimetapp®) OH (Benadryl®) NMe2 O chiral: CBS NMe2 Me N Dexbrompheniramine Reduction Chloropyramine N (Drixoral®) 99% Cl N Promethazine Cl 98% ee Cl ® Cr(CO) Cr(CO)3 Tetrahedron Lett. 1996, 37, 4837 S (Phenergan ) 3 Tetrahedron Lett. 2002, 43, 923 Baran Group Meeting Lisa M. Barton G Protein-Coupled Receptor Drugs 5/4/19 Med Chem and Process Routes: NMe CH2O 2 SH NMe2 Cl Me NH H N Me Cl HO 2 2 S O O O Cl cat H+ conc. HCl H2N POCl3 (from furfuryl) t OH 50-82% NH Bu NHtBu N n-BuLi MeS SMe MeS NHMe N 94% OH 92% 1.