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A1 Adenosine Receptor Antagonists, Agonists, and Allosteric Enhancers

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Adenosine Receptors in Health and Disease

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 193))

Abstract

Intense efforts of many pharmaceutical companies and academicians in the A1 adenosine receptor (AR) field have led to the discovery of clinical candidates that are antagonists, agonists, and allosteric enhancers. The A1AR antagonists currently in clinical development are KW3902, BG9928, and SLV320. All three have high affinity for the human (h) A1AR subtype (hA1 K i < 10 nM), > 200-fold selectivity over the hA2A subtype, and demonstrate renal protective effects in multiple animal models of disease and pharmacologic effects in human subjects. In the A1AR agonist area, clinical candidates have been discovered for the following conditions: atrial arrhythmias (tecadenoson, selodenoson and PJ-875); Type II diabetes and insulin sensitizing agents (GR79236, ARA, RPR-749, and CVT-3619); and angina (BAY 68–4986). The challenges associated with the development of any A1AR agonist are to obtain tissue-specific effects but avoid off-target tissue side effects and A1AR desensitization leading to tachyphylaxis. For the IV antiarrhythmic agents that act as ventricular rate control agents, a selective response can be accomplished by careful IV dosing paradigms. The treatment of type II diabetes using A1AR agonists in the clinic has met with limited success due to cardiovascular side effects and a well-defined desensitization of full agonists in human trials (GR79236, ARA, and RPR 749). However, new partial A1AR agonists are in development, including CVT-3619 \((\mathrm{hA}_{1}\ {\rm AR}\ {K}_{\mathrm{i}} = 55\,{\mathrm{nM,\ hA}_{\rm 2A:hA}}_{{\rm 2B:hA}_{3}}\,>\,200\):1,000:20, CV Therapeutics), which have the potential to provide enhanced insulin sensitivity without cardiovascular side effects and tachyphylaxis. The nonnucleosidic A1AR agonist BAY 68–4986 (capadenoson) represents a novel approach to angina wherein both animal studies and early human studies are promising. T-62 is an A1AR allosteric enhancer that is currently being evaluated in clinical trials as a potential treatment for neuropathic pain. The challenges associated with developing A1AR antagonists, agonists, or allosteric enhancers for therapeutic intervention are now well defined in humans. Significant progress has been made in identifying A1AR antagonists for the treatment of edema associated with congestive heart failure (CHF), A1AR agonists for the treatment of atrial arrhythmias, type II diabetes and angina, and A1AR allosteric enhancers for the treatment of neuropathic pain.

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Abbreviations

ACE:

Angiotensin-converting enzyme

ADHF:

Acutely decompensated heart failure

ALT:

Alanine aminotransferase

APD:

Action potential duration

AR:

Adenosine receptor

ARA:

(1S, 2R, 3R)-3-((trifluoromethoxy)methyl)-5-(6-(1-(5-(trifluro- methyl)pyridine-2-yl)pyrrolidin-3-ylamino)-9H-purin-9-yl) cyclopentane-1,2-diol

ARB:

Angiotensin II receptor blocker

AST:

Aspartate aminotransferase

AUC:

Area under the curve

(A–V) node:

Atrioventricular

BG9719:

(8-(3-Oxa-tricyclo[3.2.1.02, 4]oct-6-yl)-1,3-dipropyl-3, 7-dihydropurine-2,6-dione)

BG9928:

(3-(4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl) bicyclo[2.2.2]octan-1-yl)propanoic acid)

cAMP:

Cyclic AMP

Capadenoson:

(BAY 68–4986) (2-amino-6-((2-(4-chlorophenyl)thiazol-4-yl) methylthio)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3, 5-dicarbonitrile)

CHA:

N 6-Cyclohexyl adenosine

CHF:

Congestive heart failure

CHO:

Chinese hamster ovary

CK:

Creatinine kinase

CL:

Total body clearance

C max :

Maximal plasma concentration

CPA:

N 6-Cyclopentyl adenosine

CrCl:

Creatinine clearance

CV:

Cardiovascular

CVT-3619:

(2S, 3S, 4R)-2-((2-fluorophenylthio)methyl)-5-(6-((1R, 2R)-2-hydroxycyclopentylamino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol

DPCPX:

1,3-Dipropyl-8 cyclopentylxanthine

ED50 :

50% Efficient dose

F (%):

% Oral bioavailability

GFR:

Glomerular filtration rate

GR79236:

(3R, 4S, 5R)-2-(6-((1S, 2S)-2-hydroxycyclopentylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol

HF:

Heart failure

HSL:

Hormone sensitive lipase

IP:

Intraperitoneal

IPC:

Ischemic preconditioning

IV:

Intravenous

KW3902:

(3-Noradamantyl-1,3-dipropylxanthine)

L-(NAME):

N-ο-Nitro-l-arginine methyl ester

MRT:

Mean residence time

NEFA:

Nonesterified fatty acids

PVST:

Paroxysmal supraventricular tachycardia

RCM:

Radiocontrast media

RPF:

Renal plasma flow

SAR:

Structure–activity relationship

Selodenoson:

(2S, 3S, 4R)-5-(6-(Cyclopentylamino)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide)

(S–A):

Sinoatrial

SLV320:

(4-(2-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino) cyclohexanol)

t 1 ∕ 2 :

Half-life

T-62:

(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl) (4-chlorophenyl)methanone

Tecadenoson:

(2R, 3S, 4R)-2-(Hydroxymethyl)-5-(6-((R)-tetrahydrofuran-3-ylamino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol)

TG’s:

Triglycerides

T2D:

Type II diabetes

UNaV:

Urinary sodium excretion

UV:

Urine volume

V ds :

Volume of distribution

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Authors and Affiliations

  1. 14 Cambridge Center, Cambridge, MA, 02142, USA

    William F. Kiesman

  2. CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA, 94304, USA

    Elfatih Elzein

  3. Department of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA, 94304, USA

    Jeff Zablocki

Authors
  1. William F. Kiesman
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  2. Elfatih Elzein
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  3. Jeff Zablocki
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Correspondence to William F. Kiesman .

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Editors and Affiliations

  1. Endacea, Inc.,, Davis Drive 2, Research Triangle Park, 27709-2076, U.S.A.

    Constance N. Wilson

  2. Health Sciences Center, West Virginia University, Health Sciences S. 2267, Morgantown, 26506-9104, U.S.A.

    S. Jamal Mustafa

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© 2009 Springer-Verlag Berlin Heidelberg

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Kiesman, W.F., Elzein, E., Zablocki, J. (2009). A1 Adenosine Receptor Antagonists, Agonists, and Allosteric Enhancers. In: Wilson, C., Mustafa, S. (eds) Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-89615-9_2

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