Discovery and optimization of orally bioavailable and potent plasma Kallikrein inhibitors bearing a quaternary carbon

Weihe Zhang; Satish Vadlakonda; Minwan Wu; Venkat Chintareddy; L N Vogeti; Luis Juarez; Saritha Muppa; Cynthia Parker; Debra Kellogg-Yelder; Jason Williams; Kevin Polach; Xilin Chen; Krishnan Raman; Y S Babu; Pravin Kotian

doi:10.1016/j.bmc.2022.117035

Discovery and optimization of orally bioavailable and potent plasma Kallikrein inhibitors bearing a quaternary carbon

Bioorg Med Chem. 2022 Nov 1:73:117035. doi: 10.1016/j.bmc.2022.117035. Epub 2022 Sep 30.

Authors

Affiliations

¹ Department of Discovery Chemistry, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States. Electronic address: wzhang@biocryst.com.
² Department of Discovery Chemistry, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States.
³ Department of Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States.
⁴ Department of Animal Studies, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States.
⁵ Department of Discovery Bioanalytical Chemistry, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States.
⁶ Medical Writing and Regulatory Communications, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States.
⁷ Department of Computational Chemistry and Structural Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States.
⁸ Department of Discovery Chemistry, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States; Department of Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States; Department of Animal Studies, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States; Department of Discovery Bioanalytical Chemistry, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States; Department of Computational Chemistry and Structural Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States.
⁹ Department of Discovery Chemistry, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States; Department of Discovery Bioanalytical Chemistry, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States; Department of Computational Chemistry and Structural Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200, Birmingham, AL 35244, United States. Electronic address: pkotian@biocryst.com.

PMID: 36208543
DOI: 10.1016/j.bmc.2022.117035

Abstract

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50,000 individuals worldwide. Berotralstat (BCX7353) is the only small molecule approved by the US Food and Drug Administration (FDA) for the prophylactic treatment of HAE attacks in patients 12 years and older. During the discovery of BCX7353, we also identified a novel series of small molecules containing a quaternary carbon as potent and orally bioavailable Plasma Kallikrein (PKal) inhibitors. Lead compound was identified as a potent inhibitor following a detailed lead optimization process that balanced the lipophilic efficiency (LipE) and pharmacokinetic (PK) profile.

Keywords: HAE; HAE medicine; Hereditary angioedema; Lead optimization; PKal inhibitor; Plasma Kallikrein inhibitor; Quaternary carbon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angioedemas, Hereditary* / drug therapy
Angioedemas, Hereditary* / prevention & control
Antiviral Agents / therapeutic use
Carbon
Humans
Plasma Kallikrein*
United States

Substances

Antiviral Agents
Carbon
Plasma Kallikrein