Linking Disease Insights to Effective Treatment
At Somatolynk, we develop small molecule medicines to improve the lives of those affected by Alzheimer's. We build our approach on known pathological pathways to develop medicines capable of halting Alzheimer's cognitive decline and associated symptoms. Our program focuses on the development of selective somatostatin receptor targeted medicines. Somatostatin is a chemical mediator essential for brain function with potential to help mitigate underlying Alzheimer's pathology, memory loss, and neuropsychiatric symptoms through effective receptor targeting.
OVERVIEW
Somatostatin is a chemical mediator that acts through a number of receptors to regulate brain function. Loss of somatostatin and somatostatin-expressing neurons in the brain contribute to a series of pathological events driven by the accumulation of amyloid-beta peptide (Aβ) and associated oligomers (AβOs), resulting in Alzheimer's cognitive decline and dementia. Targeting of somatostatin receptors in the brain is a validated pathway of disease mitigation.
Somatostatin receptor subtype-4 (SST4) holds unique attributes. SST4 is heavily expressed in brain regions of Alzheimer's impact, with research linking its activation to the mitigation of pathology through reduction of brain Aβ and AβOs. SST4 activation is further identified in the mitigation of neuropsychiatric symptoms, seizure activity, and inflammation. Our program is advancing a number of orally bioavailable small molecule selective SST4 activators (agonist).
Target Validation
Our studies show SST4 agonist actions enhance learning and memory (T-maze, Object Rec.), with disease-modifying actions in pre-clinical AD mouse models (APPswe, 3xTg, and SAMP8) across i.c.v., i.p. and oral administration. *SST4 brain distribution between human and rodent is consistent, as is the binding domain. Using “hit” SST4 agonist NNC 26-9100, we showed i.c.v. administration increased learning (faster learning time) and decreased toxic Aβ42 oligomer expression (Fig 1) across extacellular, intracellular, and membrane fraction of extracted cortical tissue.
Lead Optimization
Early lead molecule (SM-I-26) shows excellent SST4 binding (12nM) and activity (EC50: 16.5 nM) (Fig 2), with cellular efflux ratio (p-glycoprotein) greatly reduced over previous hit compound. SM-I-26 also shows viable learning and memory benefit in the SAMP8 AD mouse model across both i.p. (T-maze and Object recognition) and i.c.v (T-maze) dosing. No negative changes in activity occurred in motor movement at any dose (Open field) or change in center zone (anxiety test). Neprilysin (enzyme that degrades Aβ and AβOs) activity was increased by single injections by i.c.v. (1ug) at 24hr post-injection, with similar trend for i.p. injection (1mg/kg) (Fig 3).
Target Innovation, Advantages, and Feasibility
The G-protein coupled receptor (GPCR) SST4 represents a novel and highly viable target, with a number of key advantages that enhance the Alzheimer's disease (AD) treatment potential:
1) A selective small molecule SST4 agonist with effective brain penetrance would foreseeably circumvent liabilities observed with many secretase inhibitors (toxicity) and antibody-based (limited brain permeability) approaches.
2) GPCR targeting to the brain with small molecules has a long history of success across numerous diseases/conditions, with established means of optimization (i.e. druggable & highly feasible).
3) SST4 is heavily expressed in the neocortex and hippocampus (particularly CA1), primary regions of AD neurodegeneration and AβO buildup, enhancing targeting to key brain regions.
4) SST4 is not expressed in the pituitary and has limited peripheral expression. SST4 agonist actions show no effect on glucagon, growth hormone, or insulin release. This holds significant advantage over other SSTs and other AβO degrading approaches, minimizing potential side-effects.
5) SST4 has a low level of receptor internalization following agonist treatment, along with a rapid rate of receptor recycling. Brain expression of SSTs also appears to be less affected in AD compared to the general decline of somatostatin over the course of the disease. This supports SST4 as a sustainable therapeutic target.
6) SST4 enhances brain neprilysin (NEP) enzymatic activity, which significantly reduces soluble AβOs, with AβOs shown to be more neurotoxic then plaques. Many investigations have repeatedly confirmed the ability of NEP to degrade monomeric-Aβ and AβOs.
7) NEP enzyme activity downstream of SST4 agonist actions helps focus the effects to the brain, reducing concerns as to effects of peripheral NEP activity.
8) Additional capacity of SST4 agonist actions to directly enhance cognition, which can help beyond early AD stages. Somatostatin administration has also shown to reverse amnesia associated with cholinergic deficits, supporting a SST4 agonist approach for used in combination with current cholinergic focused treatments (e.g. donepezil, etc.).
9) Oral and Nasal delivery focus. Oral administration is best for ease of use and patient compliance, while nasal delivery provides another delivery platform in which to enhance brain uptake.
10) A first-in-class AD drug. Our compound series is novel, patented, and exclusively licensed to Somatolynk.
PUBLICATIONS
(click publications to external links)
Crider A.M., Hospital A., Sandoval K., Neumann W., Kukielski S., Garic L., Ingold K., Dunahoo M., Srabony K., Frare R., Slater O., Peel N., Kontoyianni M. and Witt K. RSC Med Chem. 2025 Feb 19;16(2):945-960. PubMed Central PMCID.
Ashok Silwal, Austin House, Karin Sandoval, Shaluah Vijeth, David Umbaugh, Albert Crider, Shirin Mobayen, William Neumann, Ken A Witt. Neurochem Research. 2022 Mar;47(3):768-780. doi: 10.1007/s11064-021-03482-z.
Synthesis and structure-activity relationships of 3,4,5-trisubstituted-1,2,4-triazoles: high affinity and selective somatostatin receptor-4 agonists for Alzheimer's disease treatment
William L Neumann, Karin E Sandoval, Shirin Mobayen, Mahsa Minaeian, Stephen G Kukielski, Khush N Srabony, Rafael Frare, Olivia Slater, Susan A Farr, Michael L Niehoff, Audrey Hospital, Maria Kontoyianni, A Michael Crider, Ken A Witt. RSC Med Chem. 2021 May 26;12(8):1352-1365.doi: 10.1039/d1md00044f.
A structure-based approach to understanding somatostatin receptor-4 agonism (sst4)
Zhaomin Liu 1 , A Michael Crider, Daniel Ansbro, Christina Hayes, Maria Kontoyianni. J Chem Inf Model. 2012 Jan 23;52(1):171-86.doi: 10.1021/ci200375j.
Nonpeptide somatostatin agonists with sst4 selectivity: synthesis and structure-activity relationships of thioureas
S Liu 1 , C Tang, B Ho, M Ankersen, C E Stidsen, A M Crider. J Med Chem. 1998 Nov 19;41(24):4693-705.doi: 10.1021/jm980118e.