PMID- 28598634
OWN - NLM
STAT- MEDLINE
DCOM- 20170905
LR  - 20190113
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 60
IP  - 15
DP  - 2017 Aug 10
TI  - Design and Synthesis of gamma- and delta-Lactam M(1) Positive Allosteric Modulators 
      (PAMs): Convulsion and Cholinergic Toxicity of an M(1)-Selective PAM with Weak 
      Agonist Activity.
PG  - 6649-6663
LID - 10.1021/acs.jmedchem.7b00597 [doi]
AB  - Recent data demonstrated that activation of the muscarinic M(1) receptor by a 
      subtype-selective positive allosteric modulator (PAM) contributes to the 
      gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) 
      previously attributed to M(2) and M(3) 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 M(1) 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 M(1)-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 M(1) is sufficient to elicit cholinergic AEs.
FAU - Davoren, Jennifer E
AU  - Davoren JE
AUID- ORCID: 0000-0002-7312-0666
FAU - Garnsey, Michelle
AU  - Garnsey M
FAU - Pettersen, Betty
AU  - Pettersen B
FAU - Brodney, Michael A
AU  - Brodney MA
FAU - Edgerton, Jeremy R
AU  - Edgerton JR
FAU - Fortin, Jean-Philippe
AU  - Fortin JP
FAU - Grimwood, Sarah
AU  - Grimwood S
FAU - Harris, Anthony R
AU  - Harris AR
FAU - Jenkinson, Stephen
AU  - Jenkinson S
AD  - Drug Safety Research and Development, Pfizer Worldwide Research and Development , 
      La Jolla, California 92121, United States.
FAU - Kenakin, Terry
AU  - Kenakin T
AD  - Department of Pharmacology, University of North Carolina School of Medicine , 
      Chapel Hill, North Carolina 27599, United States.
FAU - Lazzaro, John T
AU  - Lazzaro JT
FAU - Lee, Che-Wah
AU  - Lee CW
FAU - Lotarski, Susan M
AU  - Lotarski SM
FAU - Nottebaum, Lisa
AU  - Nottebaum L
AD  - Drug Safety Research and Development, Pfizer Worldwide Research and Development , 
      La Jolla, California 92121, United States.
FAU - O'Neil, Steven V
AU  - O'Neil SV
FAU - Popiolek, Michael
AU  - Popiolek M
AUID- ORCID: 0000-0001-7372-1982
FAU - Ramsey, Simeon
AU  - Ramsey S
FAU - Steyn, Stefanus J
AU  - Steyn SJ
FAU - Thorn, Catherine A
AU  - Thorn CA
FAU - Zhang, Lei
AU  - Zhang L
FAU - Webb, Damien
AU  - Webb D
LA  - eng
PT  - Journal Article
DEP - 20170726
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Indans)
RN  - 0 (Isoindoles)
RN  - 0 (Lactams)
RN  - 0 
      (N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide)
RN  - 0 (Oxazoles)
RN  - 0 (PF-06827443)
RN  - 0 (Piperidines)
RN  - 0 (Receptor, Muscarinic M1)
RN  - 0 (Sulfonamides)
RN  - 0 (Thiadiazoles)
RN  - 8SSC91326P (Donepezil)
RN  - CK833KGX7E (Amphetamine)
RN  - DL48G20X8X (Scopolamine)
SB  - IM
MH  - Allosteric Regulation
MH  - Amphetamine/pharmacology
MH  - Animals
MH  - Ataxia/chemically induced
MH  - Diarrhea/chemically induced
MH  - Dogs
MH  - Donepezil
MH  - Drug Design
MH  - Female
MH  - Humans
MH  - Indans/pharmacology
MH  - Isoindoles/administration & dosage/chemical synthesis/*pharmacology/toxicity
MH  - Lactams/administration & dosage/chemical synthesis/*pharmacology/toxicity
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Microsomes, Liver/metabolism
MH  - Oxazoles/administration & dosage/chemical synthesis/*pharmacology/toxicity
MH  - Piperidines/pharmacology
MH  - Rats, Wistar
MH  - Receptor, Muscarinic M1/*agonists/antagonists & inhibitors
MH  - Scopolamine/pharmacology
MH  - Seizures/*chemically induced
MH  - Structure-Activity Relationship
MH  - Sulfonamides/pharmacology
MH  - Thiadiazoles/pharmacology
MH  - Vomiting/chemically induced
EDAT- 2017/06/10 06:00
MHDA- 2017/09/07 06:00
CRDT- 2017/06/10 06:00
PHST- 2017/06/10 06:00 [pubmed]
PHST- 2017/09/07 06:00 [medline]
PHST- 2017/06/10 06:00 [entrez]
AID - 10.1021/acs.jmedchem.7b00597 [doi]
PST - ppublish
SO  - J Med Chem. 2017 Aug 10;60(15):6649-6663. doi: 10.1021/acs.jmedchem.7b00597. Epub 
      2017 Jul 26.