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Discovery of nonpeptide 3,4-dihydroquinazoline-4-carboxamides as potent and selective sst2 agonists.

ABSTRACT: Nonpeptide sst2 agonists can provide a new treatment option for patients with acromegaly, carcinoid tumors, and neuroendocrine tumors. Our medicinal chemistry efforts have led to the discovery of novel 3,4-dihydroquinazoline-4-carboxamides as sst2 agonists. This class of molecules exhibits excellent human sst2 potency and selectivity against sst1, sst3, sst4 and sst5 receptors. Leading compound 3-(3-chloro-5-methylphenyl)-6-(3-fluoro-2-hydroxyphenyl)-N,7-dimethyl-N-{[(2S)-pyrrolidin-2-yl]methyl}-3,4-dihydroquinazoline-4-carboxamide (28) showed no inhibition of major CYP450 enzymes (2C9, 2C19, 2D6 and 3A4) and weak inhibition of the hERG channel.

SUBMITTER: Zhao J

PROVIDER: S-EPMC7508466 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Discovery of nonpeptide 3,4-dihydroquinazoline-4-carboxamides as potent and selective sst2 agonists.

Zhao Jian J Wang Shimiao S Han Sangdon S Kim Sun Hee SH Kusnetzow Ana Karin AK Nguyen Julie J Rico-Bautista Elizabeth E Tan Hannah H Betz Stephen F SF Scott Struthers R R Zhu Yunfei Y

Bioorganic & medicinal chemistry letters 20200711 17

Nonpeptide sst2 agonists can provide a new treatment option for patients with acromegaly, carcinoid tumors, and neuroendocrine tumors. Our medicinal chemistry efforts have led to the discovery of novel 3,4-dihydroquinazoline-4-carboxamides as sst2 agonists. This class of molecules exhibits excellent human sst2 potency and selectivity against sst1, sst3, sst4 and sst5 receptors. Leading compound 3-(3-chloro-5-methylphenyl)-6-(3-fluoro-2-hydroxyphenyl)-N,7-dimethyl-N-{[(2S)-pyrrolidin-2-yl]methyl} ...[more]

PMID: 32738999

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