Potent, Selective Pyrrolopyrimidine PDE11A4 Inhibitors with Improved Pharmaceutical Properties

Shams ul Mahmood; Rama Krishna Boddu; Jeremy Eberhard; Charles S. Hoffman; John Gordon; Dennis Colussi; Wayne Childers; Elvis Amurrio; Marie Danaher; Michy P. Kelly; David P. Rotella

doi:10.1021/acsmedchemlett.5c00756

Potent, Selective Pyrrolopyrimidine PDE11A4 Inhibitors with Improved Pharmaceutical Properties

Shams ul Mahmood
, Rama Krishna Boddu
, Jeremy Eberhard
, Charles S. Hoffman
, John Gordon
, Dennis Colussi
, Wayne Childers
, Elvis Amurrio
, Marie Danaher
, Michy P. Kelly
, David P. Rotella

Chemistry and Biochemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Previous work demonstrated target engagement with an orally bioavailable, potent, selective PDE11A4 inhibitor in the mouse hypothalamus. This compound was limited by low aqueous solubility, stimulating the need for alternative leads with improved pharmaceutical properties to carry out efficacy studies. This paper outlines optimization of a pyrrolopyrimidine hit leading to a potent, selective PDE11A4 inhibitor with improved pharmaceutical properties and promising activity in cell-based models of enzyme activity.

Original language	English
Pages (from-to)	547-553
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	17
Issue number	2
DOIs	https://doi.org/10.1021/acsmedchemlett.5c00756
State	Published - 12 Feb 2026

Keywords

LLPS activity
PDE11A4
cell-based activity
pharmaceutical properties
phosphodiesterase inhibitor

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10.1021/acsmedchemlett.5c00756

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title = "Potent, Selective Pyrrolopyrimidine PDE11A4 Inhibitors with Improved Pharmaceutical Properties",

abstract = "Previous work demonstrated target engagement with an orally bioavailable, potent, selective PDE11A4 inhibitor in the mouse hypothalamus. This compound was limited by low aqueous solubility, stimulating the need for alternative leads with improved pharmaceutical properties to carry out efficacy studies. This paper outlines optimization of a pyrrolopyrimidine hit leading to a potent, selective PDE11A4 inhibitor with improved pharmaceutical properties and promising activity in cell-based models of enzyme activity.",

keywords = "LLPS activity, PDE11A4, cell-based activity, pharmaceutical properties, phosphodiesterase inhibitor",

author = "Mahmood, \{Shams ul\} and Boddu, \{Rama Krishna\} and Jeremy Eberhard and Hoffman, \{Charles S.\} and John Gordon and Dennis Colussi and Wayne Childers and Elvis Amurrio and Marie Danaher and Kelly, \{Michy P.\} and Rotella, \{David P.\}",

note = "Publisher Copyright: {\textcopyright} 2026 The Authors. Published by American Chemical Society",

year = "2026",

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day = "12",

doi = "10.1021/acsmedchemlett.5c00756",

language = "English",

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journal = "ACS Medicinal Chemistry Letters",

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T1 - Potent, Selective Pyrrolopyrimidine PDE11A4 Inhibitors with Improved Pharmaceutical Properties

AU - Mahmood, Shams ul

AU - Boddu, Rama Krishna

AU - Eberhard, Jeremy

AU - Hoffman, Charles S.

AU - Gordon, John

AU - Colussi, Dennis

AU - Childers, Wayne

AU - Amurrio, Elvis

AU - Danaher, Marie

AU - Kelly, Michy P.

AU - Rotella, David P.

PY - 2026/2/12

Y1 - 2026/2/12

N2 - Previous work demonstrated target engagement with an orally bioavailable, potent, selective PDE11A4 inhibitor in the mouse hypothalamus. This compound was limited by low aqueous solubility, stimulating the need for alternative leads with improved pharmaceutical properties to carry out efficacy studies. This paper outlines optimization of a pyrrolopyrimidine hit leading to a potent, selective PDE11A4 inhibitor with improved pharmaceutical properties and promising activity in cell-based models of enzyme activity.

AB - Previous work demonstrated target engagement with an orally bioavailable, potent, selective PDE11A4 inhibitor in the mouse hypothalamus. This compound was limited by low aqueous solubility, stimulating the need for alternative leads with improved pharmaceutical properties to carry out efficacy studies. This paper outlines optimization of a pyrrolopyrimidine hit leading to a potent, selective PDE11A4 inhibitor with improved pharmaceutical properties and promising activity in cell-based models of enzyme activity.

KW - LLPS activity

KW - PDE11A4

KW - cell-based activity

KW - pharmaceutical properties

KW - phosphodiesterase inhibitor

UR - https://www.scopus.com/pages/publications/105030099864

U2 - 10.1021/acsmedchemlett.5c00756

DO - 10.1021/acsmedchemlett.5c00756

M3 - Article

AN - SCOPUS:105030099864

SN - 1948-5875

VL - 17

SP - 547

EP - 553

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 2

ER -

Potent, Selective Pyrrolopyrimidine PDE11A4 Inhibitors with Improved Pharmaceutical Properties

Abstract

Keywords

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