1387561-09-2Relevant articles and documents
Modulating physicochemical properties of tetrahydropyridine-2-amine BACE1 inhibitors with electron-withdrawing groups: A systematic study
De Cleyn, Michel,Gijsen, Harrie J. M.,Heckmann, Pauline,Hsiao, Chien-Chi,Leenaerts, Jos,Peschiulli, Aldo,Rombouts, Frederik J. R.,Van Brandt, Sven,Vos, Ann,Bache, Solène,Martinéz-Lamenca, Carolina
supporting information, (2021/12/18)
A common challenge for medicinal chemists is to reduce the pKa of strongly basic groups' conjugate acids into a range that preserves the desired effects, usually potency and/or solubility, but avoids undesired effects like high volume of distribution (Vd), limited membrane permeation, and off-target binding to, notably, the hERG channel and monoamine receptors. We faced this challenge with a 3,4,5,6-tetrahydropyridine-2-amine scaffold harboring an amidine, a key structural component of potential inhibitors of BACE1, the rate-limiting enzyme in the production of Aβ species that make up amyloid plaques in Alzheimer's disease. In our endeavor to balance potency with desirable properties to achieve brain penetration, we introduced a diverse set of groups in beta position of the amidine that modulate logD, PSA and pKa. Given the synthetic challenge to prepare these highly functionalized warheads, we first developed a design flow including predicted physicochemical parameters which allowed us to select only the most promising candidates for synthesis. For this we evaluated a set of commercial packages to predict physicochemical properties, which can guide medicinal chemists in their endeavors to modulate pKa values of amidine and amine bases.
PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease
Gopalsamy, Ariamala,Aulabaugh, Ann E.,Barakat, Amey,Beaumont, Kevin C.,Cabral, Shawn,Canterbury, Daniel P.,Casimiro-Garcia, Agustin,Chang, Jeanne S.,Chen, Ming Z.,Choi, Chulho,Dow, Robert L.,Fadeyi, Olugbeminiyi O.,Feng, Xidong,France, Scott P.,Howard, Roger M.,Janz, Jay M.,Jasti, Jayasankar,Jasuja, Reema,Jones, Lyn H.,King-Ahmad, Amanda,Knee, Kelly M.,Kohrt, Jeffrey T.,Limberakis, Chris,Liras, Spiros,Martinez, Carlos A.,McClure, Kim F.,Narayanan, Arjun,Narula, Jatin,Novak, Jonathan J.,O'Connell, Thomas N.,Parikh, Mihir D.,Piotrowski, David W.,Plotnikova, Olga,Robinson, Ralph P.,Sahasrabudhe, Parag V.,Sharma, Raman,Thuma, Benjamin A.,Vasa, Dipy,Wei, Liuqing,Wenzel, A. Zane,Withka, Jane M.,Xiao, Jun,Yayla, Hatice G.
, p. 326 - 342 (2021/01/14)
Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.
AN OXAZINE DERIVATIVE FOR USE IN THE PREVENTION OF ALZHEIMER'S DISEASE IN AT RISK PATIENTS
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Page/Page column 33; 34, (2018/02/28)
The present invention relates to an oxazine derivative BACE-1 inhibitor and pharmaceutical compositions comprising such oxazine derivative for use in the prevention of Alzheimer's disease in a patient at risk of developing clinical symptoms of Alzheimer's
