10mv

N-Alkyl & N-Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors complex with Compound 15 ((3'R)-1'-(5-amino-1-phenyl-1H-pyrazole-4-carbonyl)-6-chloro-5-fluorospiro[[3,1]benzoxazine-4,3'-piperidin]-2(1H)-one)

spinqualitylabelsall models 10mv, resolution 1.66Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 10mv is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.66Å Ligands: A1C6X, MES, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KLKB1_HUMAN Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:612423; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect. Function KLKB1_HUMAN The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. Publication Abstract from PubMed Plasma kallikrein (pKal) is a trypsin-like serine protease involved in the kallikrein-kinin, renin-angiotensin, and complement pathways, making it an attractive target for diseases, such as hereditary angioedema, diabetic mellitus complications, and cerebrovascular disorders. As part of an internal program to develop orally bioavailable small-molecule pKal inhibitors, we report lead optimization efforts within the spirocarbamate scaffold, highlighting a structure-based drug design strategy to engineer hydrogen bond interactions with N-benzyl aminopyrazoles. Additionally, mitigation of time-dependent inhibition (TDI) liability and optimization of the overall profile were achieved through a two-pronged strategy: (1) incorporating increased Fsp(3) modifications via N-alkylation and (2) leveraging torsional strain in N-aryl analogs. N‑Alkyl and N‑Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors.,Merchant RR, Chernyak N, Lopez JA, Sharp PP, Mandal M, He J, Hruza A, Rearden P, Tatosian DA, Esmay J, Yang S, Cheng AC, Ellsworth K, Ogawa A, Piou T, Fier P, Hicks J, Sinz C, Ogawa AK ACS Med Chem Lett. 2026 Feb 24;17(3):744-749. doi: , 10.1021/acsmedchemlett.6c00066. eCollection 2026 Mar 12. PMID:41847638 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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