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

Jennifer E Davoren; Michelle Garnsey; Betty Pettersen; Michael A Brodney; Jeremy R Edgerton; Jean-Philippe Fortin; Sarah Grimwood; Anthony R Harris; Stephen Jenkinson; Terry Kenakin; John T Lazzaro; Che-Wah Lee; Susan M Lotarski; Lisa Nottebaum; Steven V O'Neil; Michael Popiolek; Simeon Ramsey; Stefanus J Steyn; Catherine A Thorn; Lei Zhang; Damien Webb

doi:10.1021/acs.jmedchem.7b00597

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. Epub 2017 Jul 26.

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.

MeSH terms

Allosteric Regulation
Amphetamine / pharmacology
Animals
Ataxia / chemically induced
Diarrhea / chemically induced
Dogs
Donepezil
Drug Design
Female
Humans
Indans / pharmacology
Isoindoles / administration & dosage
Isoindoles / chemical synthesis
Isoindoles / pharmacology*
Isoindoles / toxicity
Lactams / administration & dosage
Lactams / chemical synthesis
Lactams / pharmacology*
Lactams / toxicity
Male
Mice, Inbred C57BL
Microsomes, Liver / metabolism
Oxazoles / administration & dosage
Oxazoles / chemical synthesis
Oxazoles / pharmacology*
Oxazoles / toxicity
Piperidines / pharmacology
Rats, Wistar
Receptor, Muscarinic M1 / agonists*
Receptor, Muscarinic M1 / antagonists & inhibitors
Scopolamine / pharmacology
Seizures / chemically induced*
Structure-Activity Relationship
Sulfonamides / pharmacology
Thiadiazoles / pharmacology
Vomiting / chemically induced

Substances

Indans
Isoindoles
Lactams
N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide
Oxazoles
PF-06827443
Piperidines
Receptor, Muscarinic M1
Sulfonamides
Thiadiazoles
Donepezil
Amphetamine
Scopolamine