Discovery and In Vitro Characterization of BAY 2686013, an Allosteric Small Molecule Antagonist of the Human Pituitary Adenylate Cyclase-Activating Polypeptide Receptor.

Autor: Langer G; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.) stefan.baeurle@bayer.com gernot.langer@bayer.com., Scott J; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Lind C; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Otto C; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Bothe U; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Laux-Biehlmann A; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Müller J; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., le Roy B; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Irlbacher H; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Nowak-Reppel K; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Schlüter A; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Davenport AJ; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Slack M; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.)., Bäurle S; Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany (G.L., U.B., J.M., B.l.R., S.B.); Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany (C.O., A.L.-B.); Innovation Campus Berlin, a Nuvisan Company, Berlin, Germany (H.I., K.N.-R.); Evotec SE, Hamburg, Germany (A.S., M.S.); and Evotec (UK) Ltd, Abingdon, Oxfordshire, United Kingdom (J.S., C.L., A.J.D.) stefan.baeurle@bayer.com gernot.langer@bayer.com.
Jazyk: angličtina
Zdroj: Molecular pharmacology [Mol Pharmacol] 2023 Sep; Vol. 104 (3), pp. 105-114. Date of Electronic Publication: 2023 Jun 22.
DOI: 10.1124/molpharm.122.000662
Abstrakt: The human pituitary adenylate cyclase-activating polypeptide receptor (hPAC 1 -R), a class B G-protein-coupled receptor (GPCR) identified almost 30 years ago, represents an important pharmacological target in the areas of neuroscience, oncology, and immunology. Despite interest in this target, only a very limited number of small molecule modulators have been reported for this receptor. We herein describe the results of a drug discovery program aiming for the identification of a potent and selective hPAC 1 -R antagonist. An initial high-throughput screening (HTS) screen of 3.05 million compounds originating from the Bayer screening library failed to identify any tractable hits. A second, completely revised screen using native human embryonic kidney (HEK)293 cells yielded a small number of hits exhibiting antagonistic properties (4.2 million compounds screened). BAY 2686013 (1) emerged as a promising compound showing selective antagonistic activity in the submicromolar potency range. In-depth characterization supported the hypothesis that BAY 2686013 blocks receptor activity in a noncompetitive manner. Preclinical, pharmacokinetic profiling indicates that BAY 2686013 is a valuable tool compound for better understanding the signaling and function of hPAC 1 -R. SIGNIFICANCE STATEMENT: Although the human pituitary adenylate cyclase-activating polypeptide receptor (hPAC 1 -R) is of major significance as a therapeutic target with a well documented role in pain signaling, only a very limited number of small-molecule (SMOL) compounds are known to modulate its activity. We identified and thoroughly characterized a novel, potent, and selective SMOL antagonist of hPAC 1 -R (acting in an allosteric manner). These characteristics make BAY 2686013 an ideal tool for further studies.
(Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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