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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 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 / 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 • 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 Me • Histamine is naturally produced from L- by 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 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: (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 In response to external stimuli Cl Me cell release of inflammatory Me (Claritin®) mediators such as Histamine Ph R= CO2H R R= H: Me Histamine (Benadryl Allergy 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+ (Zyrtec®) (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") • all act as inverse agonists and ; 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 – – Piperazines HO Cl – Ethylenediamines – Alkylamines – Piperidines Ways to make chiral (Levocetirizine): Select examples of H Antihistamines 1 O st 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: Cl 95% Cl Me Levocetirizine NMe2 (Dimetapp®) OH (Benadryl®) NMe2 O chiral: CBS NMe2 Me N Reduction N (Drixoral®) 99% Cl N 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. KOH MeNH2 90% O O HO O MeNO + CS 2 2 2. MeI HO NO2 NO2 Cl Cl ClMgC5H9NCH3 PPA -40 ºC HO OH Δ Cl NHMe NMe2 N N Med [BMIM][Cl] HO [Major byproduct O O2N S Chem N CN 78% N O 1,6-addition] H2SO4 HO CHO [Gives mix of O H ClMgC5H9NCH3; Process Mechanism? NMe regioisomers] HCl H2SO4 [BMIM][Cl] = 1-butyl-3-methylimidazolium chloride Green Chem. 2011, 13, 3101 91%

Cl Cl H3 Receptors Ethyl Cl N Chloroformate N HF/BF3 • Found predominantly in the central nervous system -30 ºC O • Potential therapeutic applications including obesity, memory and learning deficits, Tol, 80 ºC N 91% Alzheimer's disease, epilepsy, schizophrenia and sleep disturbance 79% • No Selective H3R drugs approved by FDA although multiple have been tested in the clinic N N • For many years all antagonists with highest potency were imidazole derivatives but these Me are too polar to penetrate blood-brain barrier –> focus now on non-imidazole antagonists CO2Et N Loratadine J. Med. Chem. 1972, 15, 750 Me JOC 1989, 54, 2242 • Similar structure found in many non-imidazole based scaffolds: basic tertiary amine (maintain ionic interaction had with imidazole) amine O R + flexible linker + lipophilic portion: H2 Receptors H3 Selective Antagonists: • Downstream signalling controls gastric acid secretion, vasodilator S N not orally CN CN • 1st potent H R antagonist was Burimamide: NH available so 2 H2N HO N wasn't put into NIS I H clinic HOAc/H2SO4 PdCl2(PPh3)2 (1 mol%) • 1st clinically approved was (Tagamet): NHMe N HO 93% HO CuI (2 mol%) NH i i NC S Pr2NH, PrOAc [For treatment of peptic ulcers and acid reflux] N N CN H Me CN 1. TsCl, TEA, DMAP Me •L-Tartrate 61% (2 Steps) N Me Other approved H2R antagonists: 2. H2N HO O NHMe NMe2 S O ABT-239 NH NH2 O N S O N K2CO3; L-Tartaric acid 2 O N S OPRD 2005, 9, 45 N S N dropped from clinical trials due to 70% H H N 2 O dangerous cardiac side effects Ranitidine NH2 (Zantac) (Pepcid) Other Clinical Candidates: N O S O N NHMe NMe2 O N O2N S AcO N NHMe Cl N N N O H H GSK-189,254 O (Wakix, approved in Europe (Tazac/Axid) (Roxit) (Alzheimer's/narcolepsy) 2016 for narcolepsy) Baran Group Meeting Lisa M. Barton G Protein-Coupled Receptor Drugs 5/4/19 O Dopamine Receptors Ergolines Agonists O NHEt R Agonists: Et2N NH • Dopamine is a catecholaminergic neurotransmitter and regulates MeS O N large variety of functions including voluntary movement, hormonal HO NH2 H NMe regulation, and hypertension H NMe2 • Indications of drugs targeting these receptors include Parkinson's, Me NMe H H R = schizophrenia, bipolar disorder, Huntington's disease, ADHD, and HO N N CH2OH or Tourette's syndrome Dopamine H H CO2H • 2 major classes that can be further divided into 5 subtypes: D1(D HN 1 HN Cabergoline and D5) and D2 (D2-D4) Pergolide fermentation products ® HN (Permax®) HN (Dostinex ) OPRD 2006, 10, 198 (Dopergin®) • Typical Antipsychotics - 1st generation, potent activity with pronounced side effects (examples include and its derivatives, , benperidol, clopenthixol, and ) Dibenzo Oxepines, Thiepines, and Azepines • Atypical Antipsychotics - 2nd generation, lower propensity for side effects; typically have activity S O H H Cl S N N against other receptors especially 5-HT (examples include , sulpiride, and ) Me Cl For a review of Dopamine Receptors see Pharmacol Rev. 2011, 63, 182 OH N N N N N N CO2H N N Antipsychotics Clozapine • Large number based on this core motif though typically not very selective (D , D , 5-HT, O N (Clozaril®) 1 2 MeN MeN MeN HRH, etc) HO2C S 1 2 Examples: R = Cl, R = Me Fumarate Olanzapine H R = H, (Compro®) (Seroquel®) (Loxitane®) (Zyprexa®) N 1 2 TiCl4 (Sparine®) S R1 N R = CF3, R = Me Process Route 50-80% R = Cl, Chlorpromazine Tetrahedron 2010, 66, 8203 N Cl ® (Stelazine®) Cu CO H 1. Na2S2O4 Me (Thorazine ) R N 2 H H 1 2 K2CO3 NH4OH R = Ac, Acepromazine R = SO2NMe2, R = Me NH2 Br N N N amyl alcohol 88% (Atravet®) Thioproperazine + NR2 ® >135 ºC 2. Xylene R = CF3 (Majeptil ) CO2H O N Cl O N Cl Δ NH NMe2 1 2 2 75-100% 2 R = Cl, R = CH2CH2OH 96% (Vesprin®) (Trilafon®) O Ways to Synthesize of Core: Ac S Ac NO2 S 1 equiv. S NH Cl N S NH2 O2N Cl 1. KOH KOH + Me2NO2S 2. Ac O Cl 2 S F3C Cl SH Cl 2 equiv. SH Cl JACS 1955, 77, 2270 NO2 KOH single isomer-only 3-Cl N NMe R R N 2 CuI NH Br ® MeN N N S N L-Proline 2 (Depixol ) 1 + R2 N ® N R1 R2 R1 R2 R (Truxal ) Thiothixene I2 K CO mix of S 2 3 I HS (Navanel®) JOC 1950, 15, 1125 90 - 110 ºC HO ® isomers O ACIE 2010, 49, 1291 OH (Clopixol ) R R S N Ph N Typically synthesized through grignard H N addition to Thioxanthone derivatives + Br BrMg NR2 2 Me H (Note that they are sold as a mixture S S Br NaOAc/ POCl3 of Z/E isomers or isomers are JACs 2003, 125, 12631 HAc reflux JOC 2007, 72, 6714 O seperated) O JOC 1961, 26, 2383 Baran Group Meeting Lisa M. Barton G Protein-Coupled Receptor Drugs 5/4/19 5-hydroxytryptamine receptors Muscarinic Receptors (mAChRs or CHRMs) • Also known as 5-HT or Serotonin receptors • Named because originally differentiated from nicotinic recepotrs by an Agonists: NH • Largest family of GPCR Neurotransmitter receptors and likely 2 increased sensitivity to Muscarine over Nicotine O Me predates evolution of muscarinic, dopaminergic, and adrenergic Agonist: Me • 5 different classes: M1,M3, M5 all couple with Gq Proteins and M2 and N+ receptors and some of oldest receptors within the rhodopsin family HO M couple with the G /G family of G Proteins Me O Me • Serotonin plays many roles (including development, cardiovascular, 4 i o • Clinically anticholinergic drugs targeting M -M have found the most Acetylcholine gastrointestinal, endocrine system, sensory perception, and range of 1 3 N use towards the treatment of chronic obstructive pulmonary disease brain functions) Me O H (COPD) and asthma N • Indications of drugs targeting these receptors include analgesics and Me Me antipsychotics Serotonin • Some of the first GPCRs to be purified and cloned Me • Involved in central and parasympathetic nervous system • 6 Families of this GPCR: 5-HT1, 5-HT2, and 5HT4-7 • Targets for multiple disease areas including Alzheimer's, schizophrenia, OH • Many drugs that target 5-HT receptors also target other GPCRs Muscarine including Dopamine Receptors (see Clozapine, Olanzapine, Parkinson's, and COPD. Quetiapine, Pergolide and related compounds, Promazine and related For a review on Muscarinic Receptors see Br. J. Pharmacol. 2011, 163, 44 compounds, Thioproperazine and related compounds) and Asian Pac. J. Trop. Dis. 2013, 3, 413 For a review on 5-HT Receptors see Chem. Rev. 2008, 108, 1614 • Blocking mAChRs can be 5-HT1D Inhibitor traced all the way back to the ancient Egyptians using Med Chem Route: NHNH2 naturally occuring NO2 NO2 anticholinergic alkaloids such as: 1. SOCl2 MeOH 1. H , Pd/C 2 O O 2. NaBH HO C NH 4 NH 2. NaNO2, HCl NH OMe Ph Ph 2 2 3. COCl O 2 SnCl2 O Cl O O KOH O O EtOH/H2O OMe O O HO MeN H MeN H H Atropine Hyoscine O N O N From Nature 2012, 482, 547 (Scopolamine) HCHO O O NaCNBH N 3 N COPD Antagonists: H H Zolmitriptan O O O O (Zolmig®, Migraines) NH Me NMe2 J. Med. Chem. 1995, 38, 3566 2 N Ph Ph O S O O S Me O OH Br O OH OH 5-HT Inhibitor Br 4 NHBn i HO S N S Pr N Me N Med Chem Route: reductive MeO Br Br amination (not Me Me Glycopyrronium Aclidinium NaOMe 4 Steps specified) MeO Ipratropium Bromide Tiotropium Bromide Bromide O NBn MeOH NBn O NCO2Et N PhO Bromide MeO 98% ® ® 55% (Atrovent ) (Spiriva ) (Robinul®) (Tudorza Pressair®) cis exclusive CO2Et Br HO MeO Br H2 Med Chem Route: Pd/C O Cl OH S O O O MgBr O S H2N 3 Steps OMe MeO S N OH OPh HN N O F H2N N CO2Et MeO OH Et O, Δ NaH N S 89% OMe O 2 S Tol, Δ 47% MeO Cisapride (Propulsid®) MeO 50% Drug Dev. Res. 1986, 8, 225 J. Med. Chem. 2009, 52, 5076 • Note: Nicotinic receptors are NOT GPCRs and instead work through a ligand-gated ion channel, differentiating them from mAChRs Baran Group Meeting Lisa M. Barton G Protein-Coupled Receptor Drugs 5/4/19 1. Adenosine Receptors (ARs) Agonist: N t N O N 1. (EtO)2POCH2CO2 Bu N Ph Ph • Adenosine produced from metabolism of ATP and plays many roles NaOH/K2CO3 NH CO2H in the body including modulation of neurotransmitter release, synaptic 2 NaOH (1:1) 83% O plasticity, neuroprotection (ie in cases of reduced blood flow, hypoxic N A N N N 2. NaOH conditions, or oxidative stress), vasoconstriction and vasodilation, T 2. SO3, DMSO N N cell proliferation, cytokine production, and bronchoconstriction N Adenosine Pyr., DCM MeOH N 79% (2 Steps) • 4 different subtypes: A1, A2A, A2B and A3. 78% FR166124 O O O • A1 (high-affinity for adenosine) and A3 (low-affinity) are inhibitory HO towards adenylyl cyclase acitivty where as A2A (high-affinity) and OPRD. 1998, 2, 320 [diuretic][high A1 selectivity] OH Developed by Fujisawa Pharma A2B (low-affinity) stimulates adenylyl cyclase and increases cyclic OPRD. 1999, 3, 394 [high H2O sol.] HO AMP (cAMP) levels. A2A Antagonists For a review of Adenosine Receptors see Chem. Rev. 2008, 108 , 238 Essential for Pyrazolo-triazolo-pyrimidines NH2 Typical Structure: A2A affinity O O A1 Antagonists • Major issue is low H2O solubility N O Me H • Changing Ar best results in N N Xanthines MeN N MeN N increasing solubility N • some of best-known but limited sucess as a lot of off-target Ar [Linker] N activity and typically suffer from low water solubility O N N O N N O N • one way to increase solubility of these types is to make Me Me Med Chem Route ticyclic imidazoline derivatives: NH2 O NH2 NH2 Caffeine Theophylline H2NHN CO2H O N N N N NH NH •H O N N O H 2 2 2 H NH •HCl H 2 1. P4S10 N N HN 1. HATU, Et3N 82% 83% + HN N pyridine, reflux Cl Cl Cl N O HN N O 2. NaOH, reflux OH H H CHO CHO O N O O N NH2 N 2. MeI, NaOH Pr O N OH Pr NSiMe3 Ar = MeO iPr (Biogen) iPr O 1. SMe NH Me SiO Me O 1. OTs 2 3 N HO H SCH-420814 NH2 TsO HMDS H H NH NaH N O 2 N N (Schering-Plough) N N DMF PrN N N 150 ºC N OH N N 2. R ArN N ArN NH OH 2. SOCl2 N O N 230 ºC N VS O N N HN 67% O N O N N NaOH Pr N Pr N 80 ºC N Mechanism? Pr reflux N Bioorg. Med. Chem. 2007, 17, 1376 BG-9928 (Biogen) Styrylxanthines ED50 = 0.01 mg/kg R = OH OMe ED = 0.01 mg/kg O O 50 H2O solubility = 1. EDC R H O solubility = 2 >100 mg/mL NH2 N OMe EtN EtN 0.1 mg/mL (Other properties also comparable J. Med. Chem. 2006, 49, 7132 HO2C OMe to BG-9928) 2. NaOH, reflux N OMe O N NH2 O N Non-Xanthine Et 35% (2 Steps) Et Istradefylline (KW-6002) MeI, K2CO3 R = H • Examples of both pyrazolo[1,5-a]pyridine and addenine derivatives being selective for A1 Bioorg. Med. Chem. 2003, 11 , 1299 Treatment of Parkinson's 90% R = Me (Kyowa Kirin Ltd.) 1. O Process Route OH•H2O A Antagonists A Antagonists H N N 2B 3 O KOH N N Ph O 3 NH2 H O/DCM O Xanthines R N 2 Ph Similar to A , Xanthine and Pyrazolo-triazolo- Me Similar to A R2 1-3 + 93% AcOH 1 N N pyrimidines derivatives can be selective for. Also N 4 Ph DME/EtOAc Antagonists changing R examples of substituted 1,4-Dihydropyridines, 2 equiv. R1-R4 can lead to O 2. NH2NH2•H2O NH O N N pyridines, and quinazoline that can inhibit (likely extra equiv. 110 ºC potent and selective serves as oxidant) A R1 O antagonists Baran Group Meeting Lisa M. Barton G Protein-Coupled Receptor Drugs 5/4/19 Opioid Receptors Chemokine Receptors

• Endrogenous Opioid Peptides (Endorphins) are hormones • Chemokines are signaling proteins secreted by cells and expressed by the CNS system and serve as neuromodulators and mediate cell migration promote a range of physiological effects including pain relief •4 families of chemokines: CXC, CC, C, and CXC (classified • All Endorphins contain common motif: Tyr-Gly-Gly-Phe-Met/Leu by cysteine resiudes in the ligand) and receptors are named sequence at the amino terminal after the chemokine it binds • Indications of drugs targeting these receptors mainly analgesic but • CXCR4 and CCR5 both have indications for HIV and CCR1 also management of diarrhea, cough, and cancer has indications in for a number of autoimmune disorders Interleukin 8 • Familys of this GPCR: Mu (µ), Delta (δ), Kappa (κ) Case Study: Maraviroc (Selzentry®) - CCR5 • µ agonists are therapeutically the most common (ie morphine, codeine, methadone, fentanyl) but also typically have the most side • Was specifically developed for potency as a CCR5 antagonist effects as µ receptors mediate respiratory depression, sedation, • Acts by stabilizing CCR5 into an inactive conformation, preventing viral entry into immune reward/euphoria, nausea, urinary retention and constipation system cells and slowing progression of disease • κ mediate dysphoric, aversive, sedative and diuretic side effects • CCR5 acts as a co-receptor for the viral • δ mediate reward, respiratory depression and convulsions envelope glycoprotein gp120 of HIV • Prolonged administration can also lead to tolerance and physical H-bond dependence with H2O • The development of opioid specific drugs that do not have adverse Hydrophobic Salt bridge side effects is of great interest for pharmaceutical companies pocket with Glu-283 µ receptor bound to β-FNA Me From Nature 2012, 485, 321 O Ph For a review on Opiod Receptors see Annu. Rev. Med. 2016, 67, 433 N N N N N AcO MeO HO H Examples of Opioid Agonists: F iPr F H-bond with Tyr-251 H-bond HO MeO H-bond with with Tyr-37 O H O OH O OH Thr-195 and SAR Thr-259 H NMe H NMe H N N O H O H Initial high thourghput AcO O O H H screen hit: NMe NMe Heroin Oxycodone Naloxone Ph N N N HO HO (antagonist) Norbinaltorphimine N Morphine Codeine (antagonist) Ph Me O HO From Science 2013, 341, 1387 Et 1. Boc O, NaHCO N Med Chem Route: 2 3 NMe2 Ph O Et HO Ph 90% Ph N N O Maraviroc Ph Ph Me HO CO2Me 2. DIBAL-H, -78 ºC CHO Ph H2N BocN O O OH 75% Methadone Fentanyl N H BnN H i H 1. PrCO2H, 1. NH2OH•HCl µ agonists Et3N, CDI, 53% Me OH pyr Anti-diarrheal 2. Na, reflux 2. POCl3, pyr; Br HN Cl N N Br Br NH2 AcNHNH ; NHMe2 Me N O BnN 2 BnN O O 2 HCl relux N SOCl2 Na2CO3 Na CO 10:1 exo:endo i O 2 3 30-50% O Pr HO Cl Ph 80 ºC O O Ph NaOH OH Ph Ph Ph Ph Ph Loperamide (Diamode®) DAST OEt Ph OEt OEt + Bioorg. Med. Chem. Lett. 2004, 14, 5275 F OH 85% F O N Cl O inseparable F F For more details on opioid drugs see Opioid Drugs 1:1 mix F NMe2 Antimicrob. Agents Chemother. 2005, 49, 4721 Group Meeting (Harwood 2019) Tetrahedron Lett. 2005, 46, 5005 Baran Group Meeting Lisa M. Barton G Protein-Coupled Receptor Drugs 5/4/19 1. iPrCOCl, Process Route: OMe OMe Na2CO3, 72% Me OMe O Me2N O 1. NH2OH•HCl O 2. PCl5, DCM, 0 ºC; O N MeOHN N NaHCO3, 95% O Cl N N AcNHNH2; AcOH N N N 1. HN 2. Na, reflux NH2 BnN MeN N BnN BnN 95% 72% N Cl O Me S N O 10% Pd/C iPr O Relugolix (Relumina®) F BnN 2 N 2. Me NH 2. PCl5, DCM, Δ H , p-TsOH Ar S 2 (Phase III trials for Outsourced i 2 i Pr Mechanism? 92% Ar Pr2NEt endometriosis and Me N Cl 44% prostate cancer, A approved in Japan) F N N (As most expensive fragment best to install at end) p-TsOH• HN Other small molecules: N F CF Me O i H 3 Pr N O F Ph O Ph OH N OMe aq. Na2CO3 CO Et S CO2Et + 2 N O H N F N F 2 93% H F O N O (made via enzymatic F F NaBH4 HO C H (outsourced) 2 O OMe resolution) F 90% F OMe N CO2H O Ph O Ph Linzagolix Elagolix (Orilissa®) A TEMPO (Phase III trials for uterine fibroids and NaBH(OAc) CHO (endometriosis) Maraviroc 3 N NaOCl, NaBr N OH Phase II for endometriosis and adenomyosis) H H OPRD 2008, 12, 1094 F F OPRD 2008, 12, 1104 F F Other GPCRs targeted by Pharmaceuticals Gonadotropin-releasing Hormone Receptors (GnRHRs) • Purinergic Receptors • Cannabinoid Receptors • GnRH is the central regulator of the reproductive hormone cascade • Targeting these GPCRs has indications for infertility, delayed puberty, contraception and • Vasopressin Receptors • GABAB Receptors hormone dependent diseases • Glucagon-like Peptide Receptors • Melanocortin Receptors • Approved agonists are all peptides (ex. Leuprolide, Goserelin) • Prostaglandin Receptors • Oxytocin Receptors • Approved antagonists are mix of peptides (ex. Cetrorelix, Abarelix) and small molecules (most • Endothelin Receptors • Somatostatin Receptors in clinical trials) • Melatonin Receptors • Tachykinin Receptors Me 1. ClCO Et, 94% • Calcium-sensing Receptors 1. NH4OAc, AcOH Me CO2Et 2 • Bradykinin Receptors Tol, reflux 2. K2CO3, KI, 93% • Metabotropic Glutamate Receptors O Cl F • Calcitonin Receptors O2N + 2. S, Et NH • Hydroxycarboxylic Acid Receptors 2 NH2 65 ºC S • Neurotensin Receptors • Cholecystokinin Receptors NC CO2Et O N 67% 2 F • Platelet-activating Factor Receptors • Free Fatty Acid Receptors • Parathyroid Hormone Receptors • Secretin Receptors CO Et 1. NBS, AIBN MeO MeN 2 Me CO2Et • Sphingosine-1-phosphate Receptors 2. MeO(CH2)2NHMe • Thromboxane Receptors CO2Et i CO Et Pr2NEt 2 N N • Luteinizing Hormone/Choriogonadotropin Receptors (LHCGRs) i S S CDI, PrNEt; 3. H2, Pd/C H2N O N • Cysteinyl Leukotriene Receptor 1 (GYSLTR1) then Ar 97% (3 Steps) 2 Ar • Follicle-Stimulating Hormone Receptors (FSHRs) MeONH2•HCl 1. NaOH, 96% • Growth-hormone-releasing Hormone Receptors (GHRHRs) MeN CO Et iPrNEt MeO 2 2. • Trace Amine-associated Receptors (TAARs) 89% H2N OMe O CO2Et • Hypocretin Receptors (also known as Orexin Receptors) N N S N MeOHN i • Thyrotropin-releasing Hormone Receptors N DEPC, Pr2NEt J. Med. Chem. 2011, 54, 4998 H Ar 3. NaOMe, MeOH, 69% • Thyroid-stimulating Hormone Receptors