ACS Medicinal Chemistry Letters最新文献_第8页

Targeted Treatment of Cancer by Using Conjugate Compounds with Poly(ADP-ribose) Polymerase (PARP) Inhibitors. 聚（adp -核糖）聚合酶（PARP）抑制剂缀合物靶向治疗癌症

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-18 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00341

Xin Zhou, Steven H Liang

引用次数: 0

Discovery of a Novel sp³‑Rich M₁ Positive Allosteric Modulators (PAMs) Chemotype via Scaffold Hopping. 通过支架跳跃发现一种新的富含sp3 - M1阳性变构调节剂（PAMs）化学型。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-17 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00271

Joseph D Bungard, Paul Spearing, Yu Nishio, Upendra Rathnayake, Chris C Presley, Sichen Chang, Haley E Kling, Analisa D Thompson, Hyekyung P Cho, Li Peng, Alice L Rodriguez, Colleen M Niswender, Olivier Boutaud, Valerie Kramlinger, Carrie K Jones, P Jeffrey Conn, Julie L Engers, Darren W Engers, Craig W Lindsley, Changho Han

{"title":"Discovery of a Novel sp3‑Rich M1 Positive Allosteric Modulators (PAMs) Chemotype via Scaffold Hopping.","authors":"Joseph D Bungard, Paul Spearing, Yu Nishio, Upendra Rathnayake, Chris C Presley, Sichen Chang, Haley E Kling, Analisa D Thompson, Hyekyung P Cho, Li Peng, Alice L Rodriguez, Colleen M Niswender, Olivier Boutaud, Valerie Kramlinger, Carrie K Jones, P Jeffrey Conn, Julie L Engers, Darren W Engers, Craig W Lindsley, Changho Han","doi":"10.1021/acsmedchemlett.5c00271","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00271","url":null,"abstract":"The M1 receptor has long been investigated as a promising CNS drug target, yet further research is essential to fully elucidate compound's Pharmacodynamic (PD) as well as Toxicokinetic (TK) effects. In this context, the development of structurally diverse and high-profile M1 PAM tool compounds remains highly valuable, as existing advanced tools exhibit notable structural similarity. One approach that can be considered during scaffold hopping exercise and can improve drug-like properties is to introduce additional sp3 carbon atoms and increase Fsp3 values; the fraction of sp3 hybridized carbons. Determining the correct location to incorporate sp3 carbon atoms can be challenging, but once the right position is identified, it often leads to novel optimization opportunities. Reported herein is the discovery of a novel sp3-rich M1 positive allosteric modulator series utilizing a N-cyclopentyl pyrazole core. Also, an iterative library synthesis approach provided an enhanced understanding of the minimum pharmacophore. Several compounds within the series showed favorable on-target potencies and DMPK properties. In conclusion, the reported sp3-rich N-cyclopentyl pyrazole-based M1 PAM scaffold offers a promising structure-activity relationship starting point to discover structurally distinct M1 PAM chemotypes.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1231-1238"},"PeriodicalIF":3.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, Synthesis, and Biological Evaluation of Ferrocenyl-Cyclo-(Gly‑l‑Pro) Hybrids Sensitizing Multidrug-Resistant Cancer Cells to Anticancer Agents. 二茂铁-环-(Gly - l- Pro)杂合体使多药耐药癌细胞对抗癌药物敏感的设计、合成和生物学评价。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-16 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00256

Andrzej Błauż, Karolina Rózga, Małgorzata Nosek, Anna Makal, Błażej Rychlik, Damian Plażuk

{"title":"Design, Synthesis, and Biological Evaluation of Ferrocenyl-Cyclo-(Gly‑l‑Pro) Hybrids Sensitizing Multidrug-Resistant Cancer Cells to Anticancer Agents.","authors":"Andrzej Błauż, Karolina Rózga, Małgorzata Nosek, Anna Makal, Błażej Rychlik, Damian Plażuk","doi":"10.1021/acsmedchemlett.5c00256","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00256","url":null,"abstract":"Ferrocenyl-cyclo-(Gly-l-Pro) hybrids as novel inhibitors of ABCB1 and ABCG2 transporters were developed. These organometallic compounds were virtually nontoxic to colon cancer cells, their multidrug-resistant (MDR) variants, and normal fibroblasts. Derivatives bearing o-, m-, or p-ferrocenylphenyl groups significantly sensitized ABCB1- and ABCG2-overexpressing cells to chemotherapeutics such as vincristine, mitoxantrone, and doxorubicin, reducing IC50 values by up to 12.7- and 10.3-fold, respectively. Notably, (S,Z)-4b, (S,Z)-4c, and (S,Z)-4d showed the strongest effects. Drug combination studies revealed synergistic interactions, particularly in vincristine-, mitoxantrone-, and etoposide-resistant cells (synergy scores: 13.6-17.05). Accumulation assays confirmed ABC transporter inhibition, with (S,Z)-4b and (S,Z)-4d increasing intracellular retention of calcein and pheophorbide A up to 3.4- and 2.9-foldcomparable to those of verapamil and Ko143. Antibody-binding assays further indicated that these hybrids act as substrates of ABCB1 and ABCG2.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1391-1400"},"PeriodicalIF":3.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel N‑Substituted Indole Derivatives as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness, and CNS Disorders. 新型N -取代吲哚衍生物作为5 -羟色胺能致幻剂用于治疗精神病、精神疾病和中枢神经系统障碍。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-16 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00346

Ram W Sabnis

引用次数: 0

IF 3.5 3区医学