2. Academic Validation
  3. Size-Reduced Macrocyclic Analogues of [Pyr1]-apelin-13 Showing Negative Gα12 Bias Still Produce Prolonged Cardiac Effects

Size-Reduced Macrocyclic Analogues of [Pyr1]-apelin-13 Showing Negative Gα12 Bias Still Produce Prolonged Cardiac Effects

  • J Med Chem. 2022 Jan 13;65(1):531-551. doi: 10.1021/acs.jmedchem.1c01708.
Kien Tran 1 2,  Xavier Sainsily 1 2,  Jérôme Côté 1 2,  David Coquerel 2 3,  Pierre Couvineau 4,  Sabrina Saibi 2,  Lounès Haroune 2,  Élie Besserer-Offroy 1 2 5,  Joël Flynn-Robitaille 2,  Martin Resua Rojas 1 2,  Alexandre Murza 1 2,  Jean-Michel Longpré 1 2,  Mannix Auger-Messier 2 3,  Olivier Lesur 2 3,  Michel Bouvier 4,  Éric Marsault 1 2,  Pierre-Luc Boudreault 1 2,  Philippe Sarret 1 2
Affiliations

Affiliations

  • 1 Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
  • 2 Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
  • 3 Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
  • 4 Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montreal H3T 1J4, Québec, Canada.
  • 5 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California 90095, United States.
PMID: 34982553 DOI: 10.1021/acs.jmedchem.1c01708
Abstract

We previously reported a series of macrocyclic analogues of [Pyr1]-apelin-13 (Ape13) with increased plasma stability and potent APJ agonist properties. Based on the most promising compound in this series, we synthesized and then evaluated novel macrocyclic compounds of Ape13 to identify agonists with specific pharmacological profiles. These efforts led to the development of analogues 39 and 40, which possess reduced molecular weight (MW 1020 Da vs Ape13, 1534 Da). Interestingly, compound 39 (Ki 0.6 nM), which does not activate the Gα12 signaling pathway while maintaining potency and efficacy similar to Ape13 to activate Gαi1 (EC50 0.8 nM) and β-arrestin2 recruitment (EC50 31 nM), still exerts cardiac actions. In addition, analogue 40 (Ki 5.6 nM), exhibiting a favorable Gα12-biased signaling and an increased in vivo half-life (t1/2 3.7 h vs <1 min of Ape13), produces a sustained cardiac response up to 6 h after a single subcutaneous bolus injection.

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