Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTMXGCW)

• DTT Name: Adrenergic receptor beta-3 (ADRB3)
• Synonyms: Beta3AR; Beta3-AR; Beta-3 adrenoreceptor; Beta-3 adrenoceptor; Beta-3 adrenergic receptor; B3AR; ADRB3R
• Gene Name: ADRB3
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: ADRB3_HUMAN
• TTD ID: T51408
• Sequence:
  MAPWPHENSSLAPWPDLPTLAPNTANTSGLPGVPWEAALAGALLALAVLATVGGNLLVIV
  AIAWTPRLQTMTNVFVTSLAAADLVMGLLVVPPAATLALTGHWPLGATGCELWTSVDVLC
  VTASIETLCALAVDRYLAVTNPLRYGALVTKRCARTAVVLVWVVSAAVSFAPIMSQWWRV
  GADAEAQRCHSNPRCCAFASNMPYVLLSSSVSFYLPLLVMLFVYARVFVVATRQLRLLRG
  ELGRFPPEESPPAPSRSLAPAPVGTCAPPEGVPACGRRPARLLPLREHRALCTLGLIMGT
  FTLCWLPFFLANVLRALGGPSLVPGPAFLALNWLGYANSAFNPLIYCRSPDFRSAFRRLL
  CRCGRRLPPEPCAAARPALFPSGVPAARSSPAQPRLCQRLDGASWGVS
• Function: Beta-3 is involved in the regulation of lipolysis and thermogenesis. Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  cGMP-PKG signaling pathway (hsa04022)
  Neuroactive ligand-receptor interaction (hsa04080)
  Endocytosis (hsa04144)
  Salivary secretion (hsa04970)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Adrenoceptors (R-HSA-390696)

Molecular Interaction Atlas (MIA) of This DTT

9 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amosulalol	DML8QSZ	Hypertension	BA00-BA04	Approved	[2]
Bitolterol	DMK6XAV	Chronic obstructive pulmonary disease	CA22	Approved	[3]
Bopindolol	DMIFYLX	Hypertension	BA00-BA04	Approved	[4]
Mepindolol	DMUDWP9	Angina pectoris	BA40	Approved	[5]
Mirabegron	DMS1GYT	Overactive bladder	GC50.0	Approved	[6]
Nipradilol	DMA65ER	Angina pectoris	BA40	Approved	[7]
Rimiterol	DMA47C6	Asthma	CA23	Approved	[1]
Trihexyphenidyl	DMB19L8	Dystonia	8A02	Approved	[8]
Vibegron	DMFR201	Overactive bladder	GC50.0	Approved	[9]

18 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ONO-2506	DMCA2PJ	Stroke	8B20	Phase 2/3	[10]
APD418	DM88IBE	Heart failure with reduced ejection fraction	BD11.2	Phase 2	[11]
ASP-3652	DM4KTN6	Overactive bladder	GC50.0	Phase 2	[12]
AZ-40140	DM9LKYP	Obesity	5B81	Phase 2	[13]
CL-316,243	DMXH1KC	Obesity	5B81	Phase 2	[14]
CP-331684	DMVO5DR	Diabetic complication	5A2Y	Phase 2	[15]
GW-427353	DMBX9C0	Urinary incontinence	MF50.2	Phase 2	[13]
LY-362884	DMD09CT	Obesity	5B81	Phase 2	[13]
LY-377604	DMZCU7I	Obesity	5B81	Phase 2	[16]
N-5984	DMUK6HC	Obesity	5B81	Phase 2	[13]
YM-430	DMKJF6H	Hypertension	BA00-BA04	Phase 2	[17]
ZD2079	DMTYD8Q	Diabetic complication	5A2Y	Phase 2	[18]
QLT-091568	DM2CDLS	Glaucoma/ocular hypertension	9C61	Phase 1/2	[19]
BMS-196085	DMTZ3A6	Diabetic complication	5A2Y	Phase 1	[20]
KUC-7483	DMTFWLE	Overactive bladder	GC50.0	Phase 1	[21]
KUL-7211	DMKFVX5	Neurogenic bladder dysfunction	GC01.4	Phase 1	[22]
Laevo-Bambuterol	DMC0VJF	Asthma	CA23	Phase 1	[23]
ZD7114	DMZQP7N	Diabetic complication	5A2Y	Phase 1	[18]

21 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Epanolol	DML1Y49	Angina pectoris	BA40	Discontinued in Preregistration	[24]
PW-2101	DMD8K3B	Angina pectoris	BA40	Discontinued in Preregistration	[25]
Amibegron	DMPS14M	Major depressive disorder	6A70.3	Discontinued in Phase 3	[26]
Adaprolol maleate-SME	DMTOCV7	Glaucoma/ocular hypertension	9C61	Discontinued in Phase 2	[27]
ALPRENOXIME HYDROCHLORIDE	DMIKLRN	Glaucoma/ocular hypertension	9C61	Discontinued in Phase 2	[28]
OBERADILOL MONOETHYL MALEATE	DMO8PN9	Hypertension	BA00-BA04	Discontinued in Phase 2	[29]
PROXODOLOL	DM8U3R6	Glaucoma/ocular hypertension	9C61	Discontinued in Phase 2	[30]
Rafabegron	DMI1SXB	Type-2 diabetes	5A11	Discontinued in Phase 2	[31]
Tienoxolol	DMLWBYO	Hypertension	BA00-BA04	Discontinued in Phase 2	[32]
NCX 950	DMNXCFZ	Asthma	CA23	Discontinued in Phase 1/2	[33]
MN-246	DM2PUYI	Urinary incontinence	MF50.2	Discontinued in Phase 1	[34]
PAFENOLOL	DM6LQGO	Hypertension	BA00-BA04	Discontinued in Phase 1	[35]
RO-16-8714	DMOVZDY	Diabetic complication	5A2Y	Discontinued in Phase 1	[36]
SB 418790	DMGHDTB	Type-2 diabetes	5A11	Discontinued in Phase 1	[37]
BMS-210285	DMMBTU6	Type-2 diabetes	5A11	Terminated	[38]
BRL 26830A	DMGX0E1	Obesity	5B81	Terminated	[39]
BRL 37344	DMS4320	N. A.	N. A.	Terminated	[40]
H-216/44	DM904UQ	Glaucoma/ocular hypertension	9C61	Terminated	[41]
SM 11044	DMF0QMD	Asthma	CA23	Terminated	[40]
SR-58878	DMS9EJ5	Irritable bowel syndrome	DD91.0	Terminated	[42]
SR-58894A	DMQUF9I	Gastrointestinal disease	DE2Z	Terminated	[43]

5 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CL-314698	DM6HADZ	Obesity	5B81	Preclinical	[13]
CP-114271	DMATUKO	Obesity	5B81	Preclinical	[13]
GCR-1087	DMFW0H9	Obesity	5B81	Preclinical	[13]
L-742791	DMK3TXY	Obesity	5B81	Preclinical	[13]
L-751250	DMOERXK	Obesity	5B81	Preclinical	[13]

25 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(-)-Ro 363	DMH6EVM	Discovery agent	N.A.	Investigative	[44]
1-(1H-Indol-4-yloxy)-3-phenethylamino-propan-2-ol	DMSUPCD	Discovery agent	N.A.	Investigative	[45]
1-(2-allylphenoxy)-3-morpholinopropan-2-ol	DMLV0PQ	Discovery agent	N.A.	Investigative	[46]
1-(2-isopropylphenoxy)-3-morpholinopropan-2-ol	DMK209P	Discovery agent	N.A.	Investigative	[46]
Carazolol	DMEKI1J	Discovery agent	N.A.	Investigative	[47]
cicloprolol	DM27S6E	Discovery agent	N.A.	Investigative	[48]
ER-23006	DMAO6JS	Asthma	CA23	Investigative	[23]
FMP-825	DMW5V9U	Diabetic complication	5A2Y	Investigative	[42]
H87/07	DM43ODJ	Discovery agent	N.A.	Investigative	[48]
iodocyanopindolol	DMOA2J8	Discovery agent	N.A.	Investigative	[49]
L-748337	DM7CPBU	Discovery agent	N.A.	Investigative	[50]
L748328	DMEGU5J	Discovery agent	N.A.	Investigative	[50]
LK 204-545	DMLVTXM	Discovery agent	N.A.	Investigative	[48]
MystiLol	DMGJYIZ	Glaucoma/ocular hypertension	9C61	Investigative	[23]
NIHP	DMDMG1O	Discovery agent	N.A.	Investigative	[48]
prenalterol	DMV8YHQ	Discovery agent	N.A.	Investigative	[51]
SB251023	DMLZDK6	Discovery agent	N.A.	Investigative	[52]
T-0509	DMSVLXQ	Discovery agent	N.A.	Investigative	[53]
Trecadrine	DMDX0VI	Discovery agent	N.A.	Investigative	[54]
Trimetoquinol	DMK9743	Discovery agent	N.A.	Investigative	[55]
xamoterol	DMOVJP3	Discovery agent	N.A.	Investigative	[56]
zinterol	DMKETL5	Discovery agent	N.A.	Investigative	[57]
[125I]ICYP	DM3BQHO	Discovery agent	N.A.	Investigative	[58]
[3H](-)CGP 12177	DMN35BY	Discovery agent	N.A.	Investigative	[59]
[3H]CGP12177	DMZN1A3	Discovery agent	N.A.	Investigative	[40]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	1.20E-01	-0.21	-1.36
Major depressive disorder	6A20	Pre-frontal cortex	7.81E-01	0.02	0.16
Irritable bowel syndrome	DD91.0	Rectal colon tissue	3.30E-01	-0.03	-0.17
Asthma	CA23	Nasal and bronchial airway	1.28E-01	-0.05	-0.2

References

• [1] Comparison of the beta2-adrenoceptor selectivity of rimiterol, salbutamol and isoprenaline by the intravenous route in man. Br J Clin Pharmacol. 1975 Feb;2(1):41-8.
• [2] Effects of amosulalol, a combined alpha 1- and beta-adrenoceptor-blocking agent, on ischemic myocardial energy metabolism in dogs. J Pharm Sci. 1993 Mar;82(3):291-5.
• [3] Bitolterol mesylate: a beta-adrenergic agent. Chemistry, pharmacokinetics, pharmacodynamics, adverse effects and clinical efficacy in asthma. Pharmacotherapy. 1985 May-Jun;5(3):127-37.
• [4] Effect of propranolol, alprenolol, pindolol, and bopindolol on beta 2-adrenoceptor density in human lymphocytes. J Cardiovasc Pharmacol. 1986;8 Suppl 6:S70-3.
• [5] Pharmacological studies on the intrinsic sympathomimetic activity of the beta-adrenoceptor antagonist mepindolol. Arzneimittelforschung. 1986 May;36(5):811-3.
• [6] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [7] Actions of nipradilol (K-351), a new alpha- and beta-adrenoceptor blocker, on the rabbit portal vein. Jpn J Pharmacol. 1984 Aug;35(4):359-69.
• [8] Obesity: pathophysiology and clinical management. Curr Med Chem. 2009;16(4):506-21.
• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [10] FR149175, a beta 3-adrenoceptor-selective agonist, is a possible therapeutic agent for non-insulin-dependent diabetes mellitus. Jpn J Pharmacol. 1997 May;74(1):109-12.
• [11] Intravenous Infusion of the beta(3)-Adrenergic Receptor Antagonist APD418 Improves Left Ventricular Systolic Function in Dogs With Systolic Heart Failure. J Card Fail. 2021 Feb;27(2):242-252.
• [12] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029610)
• [13] Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60.
• [14] Beta 3-adrenoceptor agonists as anti-diabetic and anti-obesity drugs in humans. Curr Pharm Des. 2001 Sep;7(14):1433-49.
• [15] CN patent application no. 1717230, Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor.
• [16] Combination of a Beta Adrenoceptor Modulator and a Norepinephrine-Serotonin Uptake Inhibitor for the Treatment of Obesity. ACS Med Chem Lett. 2011 August 11; 2(8): 583-586.
• [17] Cardiovascular effects of YM430, a 1,4-dihydropyridine derivative with beta-adrenoceptor blocking activity, in dogs and rats. Biol Pharm Bull. 1997 Mar;20(3):230-6.
• [18] Urinary tract toxicity in rats following administration of beta 3-adrenoceptor agonists. Toxicol Pathol. 1999 Mar-Apr;27(2):165-70.
• [19] Clinical pipeline report, company report or official report of QLT Inc.
• [20] Arylpropanolamines: selective beta3 agonists arising from strategies to mitigate phase I metabolic transformations. Bioorg Med Chem Lett. 2007 Aug 1;17(15):4290-6.
• [21] Effects of ritobegron (KUC-7483), a novel selective beta3-adrenoceptor agonist, on bladder function in cynomolgus monkey. J Pharmacol Exp Ther. 2012 Jul;342(1):163-8.
• [22] The potency of KUL-7211, a selective ureteral relaxant, in isolated canine ureter: comparison with various spasmolytics.Urol Res.2005 Dec;33(6):409-14.
• [23] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 29).
• [24] Pharmacokinetics of epanolol after acute and chronic oral dosing in elderly patients with stable angina pectoris. Br J Clin Pharmacol. 1990 Mar;29(3):333-7.
• [25] PW 2101 Penwest discontinued, USA (hypertension) Penwest non-approvable, USA (hypertension), R & D Focus Drug News. July 11, 2005
• [26] Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92.
• [27] Synthesis and pharmacological activity of adaprolol enantiomers: a new soft drug for treating glaucoma. J Ocul Pharmacol Ther. 1996 Summer;12(2):115-22.
• [28] Improved delivery through biological membranes. LVI. Pharmacological evaluation of alprenoxime--a new potential antiglaucoma agent. Pharm Res. 1991 Nov;8(11):1389-95.
• [29] US patent application no. 9,062,094, Dipeptide-based prodrug linkers for aliphatic amine-containing drugs.
• [30] The efficacy of proxodolol, a new beta-adrenoblockader with alpha-adrenoblockader properties, in its single use in patients with stable stenocardia of effort. Eksp Klin Farmakol. 1994 May-Jun;57(3):47-50.
• [31] Lack of an effect of a novel beta3-adrenoceptor agonist, TAK-677, on energy metabolism in obese individuals: a double-blind, placebo-controlled ran... J Clin Endocrinol Metab. 2007 Feb;92(2):527-31.
• [32] Effects of the beta-adrenoceptor antagonists atenolol and propranolol on human parotid and submandibular-sublingual salivary secretion. J Dent Res. 1994 Jan;73(1):5-10.
• [33] A Nitric Oxide-Releasing Salbutamol Elicits Potent Relaxant and Anti-Inflammatory Activities. JPET July 2004 vol. 310 no. 1 367-375.
• [34] CA patent application no. 630818, Pharmaceutical composition for prevention or treatment of neurogenic pain.
• [35] Presystemic elimination of the beta-blocker pafenolol in the rat after oral and intraperitoneal administration and identification of a main metabolite in both rats and humans. Drug Metab Dispos. 1993May-Jun;21(3):435-40.
• [36] The novel thermogenic beta-adrenergic agonist Ro 16-8714 increases the interscapular brown-fat beta-receptor-adenylate cyclase and the uncoupling-protein mRNA level in obese (fa/fa) Zucker rats. Biochem J. 1989 Aug 1;261(3):721-4.
• [37] News and Analysis. Nature Reviews Drug Discovery 1, 257-258 (April 2002).
• [38] CA patent application no. 509835, Nitrogen-containing heterocyclic derivatives, medicinal compositions containing the same and medicinal use thereof.
• [39] Anti-obesity and anti-diabetic actions of a beta 3-adrenoceptor agonist, BRL 26830A, in yellow KK mice. Endocrinol Jpn. 1991 Aug;38(4):397-403.
• [40] Effects of several putative beta 3-adrenoceptor agonists on lipolysis in human omental adipocytes. Int J Obes Relat Metab Disord. 1996 May;20(5):428-34.
• [41] Binding of the beta-blockers timolol and H 216/44 to ocular melanin. Exp Eye Res. 1988 Oct;47(4):565-77.
• [42] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 30).
• [43] Pharmacological characterization of beta-adrenoceptor subtypes mediating relaxation in porcine isolated ureteral smooth muscle. J Urol. 2004 Sep;172(3):1155-9.
• [44] Effects of (-)-RO363 at human atrial beta-adrenoceptor subtypes, the human cloned beta 3-adrenoceptor and rodent intestinal beta 3-adrenoceptors. Br J Pharmacol. 1997 Jan;120(2):165-76.
• [45] Synthesis and beta-adrenergic receptor blocking potency of 1-(substituted amino)-3-(4-indolyloxy)propan-2-ols. J Med Chem. 1986 Aug;29(8):1524-7.
• [46] A vHTS approach for the identification of beta-adrenoceptor ligands. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3399-404.
• [47] Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists. Eur J Clin Pharmacol. 1998 Feb;53(6):389-404.
• [48] LK 204-545, a highly selective beta1-adrenoceptor antagonist at human beta-adrenoceptors. Eur J Pharmacol. 1999 Feb 19;367(2-3):431-5.
• [49] Markedly reduced effects of (-)-isoprenaline but not of (-)-CGP12177 and unchanged affinity of beta-blockers at Gly389-beta1-adrenoceptors compared... Br J Pharmacol. 2004 May;142(1):51-6.
• [50] Potent and selective human beta(3)-adrenergic receptor antagonists. J Pharmacol Exp Ther. 1999 Aug;290(2):649-55.
• [51] Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharmacol. 1989 Mar;35(3):295-303.
• [52] Mouse beta 3a- and beta 3b-adrenoceptors expressed in Chinese hamster ovary cells display identical pharmacology but utilize distinct signalling pathways. Br J Pharmacol. 2002 Apr;135(8):1903-14.
• [53] Molecular characterization of pharmacological properties of T-0509 for beta-adrenoceptors. Eur J Pharmacol. 1996 Nov 21;315(3):363-7.
• [54] Potential anti-diabetic applications of a new molecule with affinity for beta 3-adrenoceptors. Life Sci. 1996;59(11):PL141-6.
• [55] Synthesis and human beta-adrenoceptor activity of 1-(3,5-diiodo-4- methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol derivatives in vitro. J Med Chem. 2000 Feb 24;43(4):591-8.
• [56] Binding pockets of the beta(1)- and beta(2)-adrenergic receptors for subtype-selective agonists. Mol Pharmacol. 1999 Nov;56(5):875-85.
• [57] The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. Br J Pharmacol. 2010 Jul;160(5):1048-61.
• [58] Stereoselectivity for interactions of agonists and antagonists at mouse, rat and human beta3-adrenoceptors. Eur J Pharmacol. 2004 Jan 26;484(2-3):323-31.
• [59] Binding of (-)-[3H]-CGP12177 at two sites in recombinant human beta 1-adrenoceptors and interaction with beta-blockers. Naunyn Schmiedebergs Arch Pharmacol. 2004 May;369(5):525-32.