2. Academic Validation
  3. Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity

Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity

  • J Med Chem. 2017 Aug 10;60(15):6649-6663. doi: 10.1021/acs.jmedchem.7b00597.
Jennifer E Davoren,  Michelle Garnsey,  Betty Pettersen,  Michael A Brodney,  Jeremy R Edgerton,  Jean-Philippe Fortin,  Sarah Grimwood,  Anthony R Harris,  Stephen Jenkinson 1,  Terry Kenakin 2,  John T Lazzaro,  Che-Wah Lee,  Susan M Lotarski,  Lisa Nottebaum 1,  Steven V O'Neil,  Michael Popiolek,  Simeon Ramsey,  Stefanus J Steyn,  Catherine A Thorn,  Lei Zhang,  Damien Webb
Affiliations

Affiliations

  • 1 Drug Safety Research and Development, Pfizer Worldwide Research and Development , La Jolla, California 92121, United States.
  • 2 Department of Pharmacology, University of North Carolina School of Medicine , Chapel Hill, North Carolina 27599, United States.
PMID: 28598634 DOI: 10.1021/acs.jmedchem.7b00597
Abstract

Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-120004
    M1选择性正向变构调节剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z