- Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents
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The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins.
- Londregan, Allyn T.,Wei, Liuqing,Xiao, Jun,Lintner, Nathanael G.,Petersen, Donna,Dullea, Robert G.,McClure, Kim F.,Bolt, Michael W.,Warmus, Joseph S.,Coffey, Steven B.,Limberakis, Chris,Genovino, Julien,Thuma, Benjamin A.,Hesp, Kevin D.,Aspnes, Gary E.,Reidich, Benjamin,Salatto, Christopher T.,Chabot, Jeffrey R.,Cate, Jamie H.D.,Liras, Spiros,Piotrowski, David W.
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p. 5704 - 5718
(2018/06/18)
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- Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosom
- Lintner, Nathanael G.,McClure, Kim F.,Petersen, Donna,Londregan, Allyn T.,Piotrowski, David W.,Wei, Liuqing,Xiao, Jun,Bolt, Michael,Loria, Paula M.,Maguire, Bruce,Geoghegan, Kieran F.,Huang, Austin,Rolph, Tim,Liras, Spiros,Doudna, Jennifer A.,Dullea, Robert G.,Cate, Jamie H. D.
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- SUBSTITUTED AMIDE COMPOUNDS
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The present invention is directed at substituted amide compounds, pharmaceutical compositions containing such compounds and the use of such compounds to reduce plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases, in mammals, including humans.
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- NOVEL AMIDE DERIVATIVE AND USE THEREOF AS MEDICINE
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Provided are a novel low-molecular-weight compound that suppresses production of induction type MMPs, particularly MMP-9, rather than production of hemostatic type MMP-2, as well as a prophylactic/therapeutic drug for autoimmune diseases or osteoarthritis. An amide derivative represented by the following formula (I) wherein each symbol is as defined in the specification, or a pharmacologically acceptable salt thereof.
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- IMIDAZOLE DERIVATIVES
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Described herein are compounds of formula (I) :The compounds of formula I act as DGAT1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.
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- Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
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Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein: M is CH or N; U and W are each CH, or one of U and W is CH and the other is N; X is a bond, alkylene, —C(O)—, —C(N—OR5)—, —C(N—OR5)—CH(R6)—, —CH(R6)—C(N—OR5)—, —O—, —OCH2—, —CH2O— or —S(O)0-2—; Y is —O—, —(CH2)2—, —C(═O)—, —C(═NOR7)— or —SO0-2—; Z is a bond, optionally substituted alkylene or alkylene interrupted by a heteroatom or heterocyclic group; R1 is optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, or benzimidazolyl or a derivative thereof; R2 is optionally substituted alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; and the remaining variables are as defined in the specification; compositions and methods for treating an allergy-induced airway response, congestion, diabetes, obesity, an obesity-related disorder, metabolic syndrome and a cognition deficit disorder using said compounds, alone or in combination with other agents.
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Page/Page column 53
(2010/11/27)
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