دورية أكاديمية
Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.
| العنوان: | Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors. |
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| المؤلفون: | Keylor MH; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Gulati A; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Kattar SD; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Johnson RE; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Chau RW; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Margrey KA; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Ardolino MJ; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Zarate C; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Poremba KE; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Simov V; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Morriello GJ; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Acton JJ; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Pio B; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Yan X; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Palte RL; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., McMinn SE; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Nogle L; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Lesburg CA; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Adpressa D; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Lin S; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Neelamkavil S; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Liu P; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Su J; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Hegde LG; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Woodhouse JD; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Faltus R; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Xiong T; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Ciaccio PJ; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Piesvaux J; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Otte KM; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Wood HB; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Kennedy ME; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Bennett DJ; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., DiMauro EF; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Fell MJ; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Fuller PH; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2022 Jan 13; Vol. 65 (1), pp. 838-856. Date of Electronic Publication: 2021 Dec 30. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Antiparkinson Agents/*chemical synthesis , Antiparkinson Agents/*pharmacology , Brain/*metabolism , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/*antagonists & inhibitors , Quinazolines/*chemical synthesis , Quinazolines/*pharmacology, Antiparkinson Agents/pharmacokinetics ; Biological Availability ; Drug Design ; Humans ; Models, Molecular ; Protein Kinase Inhibitors/pharmacology ; Quinazolines/pharmacokinetics ; Structure-Activity Relationship |
| مستخلص: | The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24 . These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models. |
| المشرفين على المادة: | 0 (Antiparkinson Agents) 0 (Protein Kinase Inhibitors) 0 (Quinazolines) EC 2.7.11.1 (LRRK2 protein, human) EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2) |
| تواريخ الأحداث: | Date Created: 20211230 Date Completed: 20220207 Latest Revision: 20220207 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/acs.jmedchem.1c01968 |
| PMID: | 34967623 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.1c01968 |